1. Introduction
With approximately 19 million new cases worldwide and an estimated 10 million cancer-related deaths in 2020, cancer represents one of the leading causes of mortality, heavily impacting patients’ quality of life and resulting in substantial socioeconomic ramifications [ 1 ]. Ongoing research continues to unveil the various molecular mechanisms behind oncogenesis. Complex pathways that encompass a multitude of molecules are implicated in a variety of processes that drive different types of tumors. Defining their role is considered of utmost importance, as it holds the key to the development of novel, personalized, and more effective therapeutic interventions. Epigenetic mechanisms, shaping the ever-changing landscape of a cell’s gene expression, are viewed as one of the main factors driving neoplasia. More specifically, the role of proteins implicated in DNA packaging and the proteins associated with them has become the research subject of a plethora of scientists who have attempted to shed light on their implications in gene expression and, ultimately, carcinogenesis. Among them, death domain-associated protein (DAXX) and Holliday junction recognition protein (HJURP) are two of the most extensively studied biomolecules due to their central contribution in a variety of epigenetic modifications implicated in neoplasia ( Figure 1 ).
DAXX interacts with the H3.3/H4 dimer acting as a H3.3 histone chaperone [ 2 , 3 ]. Apart from its role as a H3.3 specific histone chaperone, it is also part of several molecular signaling pathways, including the FAS-DAXX-apoptosis signal-regulating kinase 1 (ASK1)-mitogen-activated protein 2 kinase (MAP2K) axis that induces apoptosis [ 4 , 5 , 6 ] and the DNA-damage-induced p53 activation [ 2 ]. HJURP acts as a centromere protein A (CENPA) histone chaperone, aiding its deposition during the late mitosis/early G1 phase of the cell cycle [ 7 ]. HJURP plays a vital role in safeguarding chromosome stability. On the other hand, its overexpression, induced by p53 mutations, is linked to ectopic deposition of CENP-A and tumor-promoting properties in various organs [ 7 ].
DAXX and HJURP are implicated in a multitude of cellular processes, including telomere lengthening, cell apoptosis, chromosome stability, and regulation of various oncogenes’ expression, all of which play key roles both in tumorigenesis and tumor suppression. Interestingly, DAXX and HJURP can either promote or hinder most of the aforementioned mechanisms, acting ultimately either as pro- or anti-tumorigenic factors, depending on the organ of origin or the specific type of tumor. Figure 2 is indicative of the diverse effects of DAXX and HJURP in tumorigenesis, as they can undertake a protective or aggravating role depending on the tissue of origin. DAXX acting either as a pro-apoptotic or an anti-apoptotic factor, contingent on the cell type and context, is a mere example of the complexity of these biomolecules’ role in cancer [ 8 ].
In the current review, we aim to document the studies investigating the association between DAXX and HJURP expression with human neoplasia of various tissues, as well as the possible correlations with clinicopathological parameters [ 9 ]. More specifically, we will try to decipher whether DAXX and HJURP are over- or under-expressed in solid tumors and hematologic neoplasms and whether the different expression patterns are linked to clinicopathological parameters, and we assess their utility as tools for diagnosis and prognostic biomarkers, as well as their possible application in therapy monitoring. We will also explore their role as potential targets for the development of novel, personalized therapeutic strategies. This review focuses on published research studying DAXX and HJURP expression either on mRNA or protein level in human tissue samples. Of note, we do not include studies conducted on non-human tissue specimens, xenograft models, and cell lines alone. The majority of the studies presented applied the methods of immunohistochemistry (IHC), IHC in tissue microarrays (TMA IHC), Western blot, reverse transcription polymerase chain reaction (RT-PCR), quantitative PCR (qPCR), next-generation sequencing (NGS), and whole-genome sequencing (WGS) to assess DAXX and HJURP protein or mRNA expression in malignant tissues and non-malignant control specimens. Researchers evaluated the presence or absence of expression, the expression patterns, the levels of expression and staining intensity along with the different expression patterns and protein localization (nuclear, cytoplasmic, or membranous). These results have been correlated with a number of clinicopathological parameters, including tumor histological grade, disease pathological stage, and patients’ disease-free survival (DFS) and overall survival (OS).
2. Head and Neck, Thymus, and Skin Tumors
2.1. Brain
Five studies in total investigated the impact of DAXX expression in brain tumors, often yielding contradictory results ( Table 1 ). Cavalcante et al. reported the presence of significantly higher DAXX expression in grade 2 and grade 3 meningiomas compared to those classified as grade 1 [ 10 ]. Regarding glioblastoma multiforme (GBM) patients’ OS, alterations in DAXX genes associated with longer OS in the study conducted by Cantero et al. [ 11 ] and loss of DAXX expression has been linked to shorter OS by S. Ak Aksoy et al. [ 12 ]. On the other hand, DAXX mutated neuroblastoma (NBL) cases exhibited poorer outcome due to increased chemotherapy resistance [ 13 ]. Finally, alterations in DAXX expression often led to alternative lengthening of telomeres (ALT), a feature that in many cases bears important clinical impact. However, no significant differences in the clinicopathological characteristics of the group with abnormally shortened telomeres compared to the group with normal telomeres have been observed in pituitary adenoma cases [ 14 ].
HJURP seems to play an overall tumor-promoting role in brain carcinogenesis. In a large study that incorporated 267 malignant glioma specimens, HJURP overexpression correlated with poorer patients’ OS [ 15 ]. Similarly, two more studies reported the link between lower OS and HJURP upregulation in brain tumor cases [ 16 , 17 ].
In conclusion, DAXX exerts a tumorigenic role in brain carcinogenesis ( Figure 2 ) and constitutes, furthermore, a potential diagnostic biomarker for tumor grade assessment, as well as an indicator of prognosis, specifically in the fields of patients’ OS and expected response to therapy ( Figure 3 ). Similarly, HJURP exhibits tumor-promoting properties in brain tumorigenesis ( Figure 2 ), with its expression linked to patients’ poorer OS ( Figure 3 ).
2.2. Oral Cavity
Both DAXX and HJURP expression was reported upregulated in oral cancer tissue specimens compared to non-tumorous control samples [ 18 , 19 ], with HJURP overexpression exhibiting further association with patients’ age and shorter OS [ 19 ]. Therefore, DAXX and HJURP seem to promote carcinogenesis of the oral cavity ( Figure 2 ), with HJURP level of expression exhibiting prognostic value as well, with its upregulation linked to grimmer outcomes ( Figure 3 ).
2.3. Thymus
In thymic epithelial tumor (TET) patients, increased cytoplasmic HJURP expression associated with advanced Masaoka–Koga stage and its presence correlated with lymphocyte-poor TETs [ 20 ]. Further research is called for to investigate the potential tumor-promoting role of HJURP in TETs as well as its diagnostic value ( Figure 3 ).
2.4. Skin
The only study exploring the role of HJURP in skin tumors concerned melanomas, included a large sample of 458 cases and underlined its tumorigenic properties, as not only was HJURP overexpressed in tumor tissues compared to normal ones, but it also revealed the link between its upregulation and shorter patients’ OS [ 21 ]. Therefore, HJURP appears to promote the development of skin melanocytic lesions ( Figure 2 ) and to constitute a herald of poorer patients’ prognosis ( Figure 3 ).
3. Lung, Breast, and Sarcomas
3.1. Lung
High DAXX expression has been associated with lower OS in lung adenocarcinoma (AC) patients, although not significantly ( p = 0.216), while high concomitant DAXX and ATRX expression has been associated with better OS in these patients [ 22 ].
On the other hand, the role of HJURP in lung carcinogenesis has been more extensively investigated, with four studies reporting the association between its overexpression and lower patients’ OS [ 23 , 24 , 25 , 26 ], and two of them further correlating it with higher TNM disease stage [ 25 , 26 ].
It is, therefore, evident that more research is needed to shed light on the possible tumorigenic role of DAXX in lung AC ( Figure 2 and Figure 3 ). Meanwhile, HJURP exhibits a clear negative effect in neoplastic disease of the lung, further serving as a potential biomarker for disease staging and patients’ prognosis ( Figure 2 and Figure 3 ).
3.2. Breast
In a large study that included 220 breast cancer (BC) cases, DAXX expression correlated with tumor grade, necrosis, vascular invasion, and positive hormonal receptor status. Low levels of DAXX expression associated with lower DFS but not OS [ 27 ]. In solid papillary carcinoma (SPC) patients, loss of DAXX expression was significantly associated with lymphatic invasion [ 28 ].
Four studies in total underline the tumor-promoting role of HJURP in BC specimens. Bravaccini et al. reported a greater than sevenfold risk of relapse in patients highly expressing HJURP in the stroma of in situ breast carcinoma specimens [ 29 ]. Milioli et al. focused on the different patterns of HJURP expression in basal-like breast cancer (BLBC) cases, observing high levels of HJURP expression in basal II basal-like subtype (BL2) specimens [ 30 , 31 ]. This observation possibly has a significant impact on clinical decision making and planning of optimal therapeutic strategy, as BL1 and BL2 subtypes exhibit higher expression of cell cycle and DNA damage response genes and representative cell lines preferentially responded to cisplatin. Moreover, high HJURP mRNA levels were significantly associated with estrogen-receptor and progesterone-receptor negative status, advanced Scarff–Bloom–Richardson grade, younger age at diagnosis, Ki67 proliferation indices, and shorter DFS and OS [ 32 ]. Montes de Oca et al. also correlated high HJURP mRNA levels with shorter patients’ DFS along with lower distant metastasis-free survival, higher possibility of developing metastasis, and shorter OS in the luminal A subtype cases [ 33 ].
As a conclusion, DAXX appears to exert a protective role in BC ( Figure 2 ), exhibiting value as a prognostic biomarker as well ( Figure 3 ). On the other hand, HJURP negatively impacts neoplastic disease of this specific organ, potentially aiding in disease precise diagnosis and prognosis ( Figure 2 and Figure 3 ).
3.3. Sarcomas
In a study that included 106 angiosarcoma specimens, all tissue samples retained DAXX immunoexpression, while no association between its levels and clinicopathological parameters was observed [ 34 ]. On the contrary, DAXX immunoexpression was observed as significantly higher in chondrosarcoma than in osteochondroma tissues, and positive DAXX expression positivity associated with shorter patients’ OS [ 35 ]. DAXX gene methylation has been detected in leiomyosarcoma (LMS) specimens [ 36 ] and, in a similar study, none of the 92 LMS cases lost DAXX immunoexpression [ 37 ]. In gastrointestinal stromal tumors (GISTs), only 3.3% of cases showed loss of DAXX immunoexpression and telomere dysregulation (defined as telomerase reverse transcriptase (TERT) promoter mutations or loss of either ATRX or DAXX expression) was frequently seen in GISTs of non-gastric origin but did not statistically correlate with any clinicopathological characteristics, DFS or OS [ 38 ].
Data on HJURP expression in human bone and soft tissue tumors remains limited, as only one study currently exists that investigated its levels in 58 synovial sarcoma (SS) cases. The scientists reported that HJURP gene is over-expressed in SS tissues, along with four other genes, namely non-SMC condensin I complex subunit G (NCAPG), Xenopus kinesin-like protein 2 (TPX2), CENPA, and NDC80 [ 39 ].
Therefore, DAXX role is designated as tumorigenic in a subset of sarcomas, namely chondrosarcomas, with a potential role as a biomarker of grim prognosis ( Figure 2 and Figure 3 ). Similarly, HJURP appears to play a tumor-promoting role in SSs ( Figure 2 ).
Table 2 summarizes the results of the studies carried out on DAXX and HJURP expression in lung and breast tumors as well as sarcomas.
4. Gastrointestinal Tract, Liver, Biliary Tract, and Pancreas
4.1. Esophagus
Ko et al. examined DAXX immune expression in 60 esophageal squamous cell carcinoma (ESCC) specimens using adjacent non–tumorous tissue samples as controls and reported that while DAXX immunostaining remained negative or weak in normal tissues, in cancerous samples it associated with lymph node metastasis, American Joint Committee on Cancer (AJCC) stage, distant metastasis and OS in patients with stage IIB and stage IV disease [ 40 ]. In accordance with these results are the ones observed by Yuen et al., who correlated DAXX immunoexpression with nuclear DJ-q expression. The latter was significantly higher in ESCC and lymph node metastases tissues and associated with shorter OS and higher tumors’ metastatic potential [ 41 ].
Overall, DAXX upregulation is designated as a tumor-promoting factor in ESCCs ( Figure 2 ) and could be utilized in the fields of disease staging, tumor grading, and assessment of OS ( Figure 3 ).
4.2. Stomach
Chen et al. stressed the importance of DAXX protein subcellular localization in neoplastic tissues. Interestingly, in their study that incorporated 323 gastric cancer (GC) cases, cytoplasmic DAXX expression was associated with a longer OS and DFS, while high nuclear DAXX expression suggested a poorer OS [ 42 ]. Similarly, one more study highlighted that it was the DAXX Nuclear/Cytoplasmic ratio (NCR) that was associated with cancerous tissues. More specifically, in normal gastric mucosal cells, DAXX was expressed in the cytoplasm but was absent in the nucleus. Cells with intestinal metaplasia appeared to express DAXX in both the nucleus and the cytoplasm, and in tumor cells, DAXX exhibited only nuclear expression [ 43 ]. Moreover, a high DAXX NCR ratio was associated with shorter DFS and OS.
In conclusion, nuclear DAXX overexpression exerts a tumorigenic role in GC ( Figure 2 ), while it also associates with poorer overall prognosis ( Figure 3 ).
4.3. Colon
The role of DAXX in the field of colon carcinogenesis appears to be controversial, as 3 studies attribute tumor-suppressive properties to DAXX [ 44 , 45 , 46 ] while one group of researchers report it as a tumorigenic factor [ 47 ]. DAXX expression was found significantly lower in colorectal carcinoma (CRC) cases with positive serum carcinoembryonic antigen (CEA) screening results (defined as serum CEA levels of >5 ng/mL) compared to patients with negative CEA screening levels. Moreover, DAXX expression was significantly correlated with CD24 expression. Specifically, reduced DAXX expression was associated with reduced CD24 expression in CRC samples [ 44 ]. DAXX might be considered a potential regulator of CD24 or β-catenin expression, which may be correlated with the proliferative and metastatic potential of CRC. A significant increase in proliferation was observed in DAXX-knockdown CRC cells compared with the negative controls. DAXX knockdown significantly increased 293 T and Hct116 cell migration, suggesting that, indeed, DAXX may play a protective role in CRC [ 44 ]. Similarly, Liu et al. explored the expression of DAXX in 8 pairs of matched primary CRC tissue and liver metastatic CRC tissue samples, reporting it lower in liver metastases than in primary CRC tissues [ 45 ]. These results suggest a possible association between DAXX downregulation and CRC metastasis. Additionally, Tzeng et al. observed reduced DAXX expression in CRC tissues compared to normal colon tissues [ 46 ]. On the other hand, Huang et al., utilizing both IHC and qRT-PCR, reported higher DAXX expression in CRC specimens compared to non–neoplastic ones [ 47 ]. It is therefore clear that further studies are required to elucidate the complex effects of DAXX in colon carcinogenesis.
Interestingly, HJURP also seems to act as a tumor suppressor in this specific organ. Kang et al. conducted immunohistochemical studies in 162 CRC cases and observed a beneficial role of high HJURP expression in tissues to CRC patients’ OS [ 48 ].
To conclude, DAXX has been reported as exerting both tumor-promoting and tumor-suppressing properties in CRC ( Figure 2 ), while HJURP appears to play a protective role and was correlated with longer OS ( Figure 2 and Figure 3 ).
4.4. Liver
Retrieving data from the cancer genome atlas (TCGA) and the Gene Expression Omnibus (GEO) datasets, Ding et al. reported that the mRNA expression of 9 genes in total, namely enhancer of zeste homolog 2 ( EZH2 ), cyclin-dependent kinase 1 ( CDK1 ), CENPA , RD54-like ( RAD54L ), PDZ binding kinase ( PBK ), helicase, lymphoid specific ( HELLS ), HJURP , aurora kinase A ( AURKA ), and aurora kinase B ( AURKB ), was associated with hepatocellular carcinoma (HCC) patients’ OS as well as invasion depth of tumor and distant metastasis [ 49 ]. In accordance with these findings, another group of researchers observed higher HJURP expression in HCC tissues compared to adjacent normal ones as well as HJURP upregulation in tissues of patients with advanced HCCs compared to those of patients with early-stage disease. Moreover, HJURP overexpression was associated with poor patients’ DFS and OS [ 50 ]. Similarly, Hu et al. investigated HJURP mRNA and protein expression through the methods of real-time PCR and IHC, reporting that high HJURP expression was significantly associated with tumor size (tumors >5 cm), Barcelona clinic liver cancer stage, tumor number, tumor differentiation, TNM stage and poorer patients’ OS [ 51 ].
It is evident that HJURP enhances liver neoplastic process ( Figure 2 ) and can potentially aid in disease TNM staging, tumor grading as well as serve as a prognostic marker for patients’ DFS and OS ( Figure 3 ).
4.5. Biliary Tract
The role of HJURP in biliary tract neoplasia was investigated by Yang et al. who reported increased HJURP expression in cholangiocarcinoma (CCA) tissue samples compared to non-tumorous ones. Additionally, HJURP overexpression was associated with lower OS in cases of intrahepatic and perihilar CCA but not in patients with distal CCA [ 52 ]. Thus, the study highlights the potential role of HJURP as a tumor-promoting factor ( Figure 2 ) and a marker of worse prognosis ( Figure 3 ) in CCAs.
4.6. Pancreas
The contribution of DAXX in pancreatic neuroendocrine tumors (PanNETs) is undoubtedly among the most extensively studied. While it has been the subject of a considerable number of studies, no contradictory results have been reported, with researchers agreeing on the overall tumor-promoting role of DAXX loss in pancreas tumorigenesis [ 53 , 54 , 55 , 56 , 57 , 58 , 59 , 60 , 61 , 62 , 63 , 64 , 65 , 66 , 67 , 68 , 69 ].
Jiao et al., based on a sample comprising 68 sporadic PanNET specimens, detected mutations of DAXX genes in 12 out of 68 cases, which were associated with better patients’ OS [ 53 ]. One possible explanation for the difference in survival is that mutations in multiple endocrine neoplasia type 1 ( MEN1 ) and DAXX / ATRX identify a biologically specific subgroup of PanNETs. Another group of researchers conducted IHC studies in large sample comprising 1322 neuroendocrine tumors (NETs) in total that included 561 primary nonfunctional PanNETs (NF-PanNETs), 107 NF-PanNET metastases and 654 primary, non-pancreatic non-functional NETs and NET metastases. Loss of DAXX was correlated with the presence of distant metastases/recurrence and DFS rates were shorter in patients with small NF-PanNETs (≤2.0 cm) with DAXX loss. Moreover, only a small subset of pulmonary carcinoids exhibited DAXX loss. Therefore (loss of) DAXX emerges a potential highly specific diagnostic biomarker to indicate the possibility of a pancreatic primary tumor [ 54 ]. Ueda et al. carried out IHC studies in 44 PanNET specimens and observed that low DAXX expression correlated with nonfunctional tumors, higher Ki-67 index, World Health Organization (WHO) grade G2 tumors, higher recurrence rate, worse patients’ DFS and presence of synchronous liver metastasis, although insignificantly ( p = 0.081) [ 55 ]. Interestingly, in a study that incorporated 13 pancreatic neuroendocrine neoplasm (NEN) specimens (4 G1, 5 G2, and 4 G3 tumor samples), DAXX exhibited lower mRNA expression in the tumor relative to that in the non-tumor tissue in G1 and G2 specimens. In contrast, G3 samples exhibited higher DAXX mRNA expression in tumor tissues relative to non-tumorous ones. Additionally, DAXX IHC staining was absent in non-tumor, G1 and G2 tumor tissues, while strong nuclear staining was observed in less than 25% of cells in G3 tumor tissues [ 56 ]. DAXX mutation was identified in 13 out of 51 cases (25%) of 51 neuroendocrine liver metastases specimens, and the presence of DAXX mutation was associated with shorter hepatic progression-free survival (PFS) [ 57 ]. Park et al. reported that loss of DAXX protein expression was associated with poor patients’ OS. However, in the subgroup of cases with metastatic PanNETs, it was correlated with longer OS rates [ 58 ]. This observation is in accordance with the one made by Kim et al., who also reported that although loss of ATRX/DAXX expression was associated with reduced DFS, in patients with distant metastases, the loss of ATRX/DAXX expression was associated with better OS [ 65 ]. The link between loss of DAXX expression and DAXX mutations with lower patients’ DFS or OS was highlighted by three more studies [ 59 , 60 , 61 ]. On the other hand, in PanNET specimens from patients with Von Hippel-Lindau (VHL) syndrome, no statistically significant difference in tumor DAXX protein expression by pathologic diagnosis, clinical data, VHL exon mutation, and functional imaging results was identified [ 62 ]. Additionally, the loss of DAXX expression was correlated not only with shorter DFS rates [ 63 ] but also with postoperative hepatic recurrence [ 63 ] and an increased risk of metastasis [ 64 ]. Likewise, the loss of DAXX IHC expression was observed in 64 out of 100 cases of grade 1 and 2 primary PanNET specimens [ 66 ] and 16/105 PanNET specimens in a similar study [ 67 ] which reported that while the loss of DAXX expression alone did not significantly correlate with poor patients’ OS, the loss of either DAXX or ATRX was associated with higher Ki67 proliferative index, high tumor grade, nodal involvement, higher disease stage, infiltrative borders, and lymphovascular invasion. Similarly, the loss of ATRX/DAXX immunohistochemical expression was identified in 18/46 cases of PanNET tumors and was correlated with tumor size larger than 5 cm [ 68 ]. Lastly, Chen et al. examined not only NET specimens but also pancreatic adenocarcinoma (PDAC) samples in their study. The loss of DAXX expression was detected in 29.9% of all NET cases but not in any of the non-neoplastic pancreatic tissues or PDACs and was overall associated with Ki-67 index and higher histologic tumor grades [ 69 ].
In pancreatic tumors, HJURP expression has only been investigated in PDAC specimens and was observed significantly higher in cancerous tissues than in adjacent normal ones. Furthermore, it was linked to poor patients’ OS [ 70 ].
In conclusion, DAXX exerts an undisputed protective role in pancreatic NET tumorigenesis, with DAXX loss and ALT comprising the driving force behind this type of neoplastic process ( Figure 2 ). Moreover, researchers have underlined the utility of DAXX as a diagnostic biomarker for assessing disease TNM stage and tumor grade as well as predicting patients’ DFS and OS ( Figure 3 ). On the contrary, HJURP exhibits a tumorigenic role in PDAC ( Figure 2 ) and has been linked to worse disease outcome ( Figure 3 ).
The data from studies conducted investigating the role of DAXX and HJURP in the gastrointestinal tract, liver, biliary tract, and pancreas carcinogenesis are presented in Table 3 .
5. Urinary Tract, Prostate, Testis, and Adrenal Glands
5.1. Kidney
DAXX loss of expression, although almost always observed in studies investigating PanNET specimens, was absent in primary renal NET cases [ 71 ].
Researchers who conducted studies on HJURP expression in clear cell renal cell carcinoma (ccRCC) specimens reported contradictory results regarding its role in tumorigenesis. More specifically, Wei et al. associated its overexpression with reduced patients’ DFS and OS [ 72 ]. On the other hand, one study observed no association between HJURP expression and clinicopathological parameters [ 73 ] and another detected lower HJURP expression in RCC tissues compared with that in the adjacent paracancerous ones [ 74 ]. In contrast, Zhang et al. reported it as upregulated in ccRCC tissues compared to normal ones and further associated HJURP expression with TNM stage, histopathological grade, and poorer patients’ OS [ 75 ]. Moreover, HJURP levels of expression were correlated with infiltration of various immune cells and expression of a wide range of immunocyte gene markers, showing that HJURP plays an essential role in the tumor microenvironment by regulating immunocyte infiltration [ 75 ].
Overall, one study investigated through qRT-PCR and Western blot the expression of HJURP and reported it was lower in ccRCC tissues compared with that in the adjacent paracancerous ones [ 74 ]. Another study, based on the data collected from TCGA database from 52 ccRCC samples, observed no association between HJURP expression and clinicopathological parameters [ 73 ]. Finally, two studies that also retrieved data from TCGA database and incorporated 955 ccRCC tumor specimens in total attributed tumorigenic properties to HJURP overexpression [ 72 , 75 ]. Therefore, it is possible that aberrations in HJURP expression are implicated in kidney carcinogenesis, which include both down- and upregulated expression in tumor tissues.
Therefore, DAXX does not seem to participate in renal carcinogenesis, with the role of HJURP still remaining unclear as far as neoplastic processes of the kidney are concerned ( Figure 2 ).
5.2. Bladder
DAXX IHC expression was observed in 90% of urothelial carcinoma (UC) nuclei compared to 70% of normal urothelium nuclei. Moreover, in UC tissues, nuclei adjacent to the stroma exhibited slightly lower expression than in the intermediate cell layers, whereas in normal urothelium tissues, expression was slightly greater compared to the intermediate and superficial cell layers [ 76 ]. Based on their observations, the authors suggest the presence of altered protein expression of DAXX in UC and in its preinvasive phases. In small cell bladder carcinoma specimens, the loss of DAXX expression was detected in five (16.1%) cases, including four patients who presented with limited stage disease. All four patients who presented with limited-stage disease underwent chemotherapy and remained alive during follow-up, implying that loss of DAXX may sensitize tumor cells to chemotherapy [ 77 ].
Therefore, it is evident that DAXX exerts an overall tumorigenic role in bladder cancer ( Figure 2 ).
5.3. Prostate
Kwan et al. reported higher DAXX expression in prostate cancer tissues and DAXX overexpression was associated with tumor Gleason score and the presence of metastasis [ 78 ]. Likewise, DAXX expression was observed as significantly increased compared to both normal adjacent tissues and benign prostate hyperplasia samples by Jamali et al. [ 79 ]. Another study found that high DAXX expression correlated with transmembrane protease, serine 2 (TMPRSS2)/ERG rearrangement, ERG expression, high tumor Gleason grade, advanced pT stage, high Ki-67 labeling index, and early prostate-specific antigen (PSA) recurrence [ 80 ]. Lastly, Lorena et al. reported DAXX mRNA levels as increased in metastatic prostate cancer tissues but low in normal prostate glands, and increased DAXX expression was associated with higher tumor Gleason scores and lower patients’ OS [ 81 ].
HJURP was also reported as overexpressed in prostate cancer tissues compared with benign prostate tissues, and high HJURP expression was associated with positive PSA levels, high Gleason score, advanced pathological stage, presence of metastasis, PSA failure, and shorter biochemical recurrence-free survival [ 82 ]. Luo et al. also observed a link between the lower biochemical recurrence-free survival and high HJURP expression [ 83 ].
In conclusion, both DAXX and HJURP are implicated in prostate carcinogenesis ( Figure 2 ), with their overexpression appearing to hold value for disease staging and tumor grading as well as patients’ prognosis, in the case of DAXX ( Figure 3 ).
5.4. Adrenal Glands
Mete et al. reported that the global loss of DAXX expression was associated with longer patients’ DFS in adrenal cortical carcinoma cases, suggesting a possible tumorigenic role of the aforementioned molecule in adrenal gland carcinogenesis [ 84 ] ( Figure 2 ).
Table 4 summarizes the results from studies investigating DAXX and HJURP expression in tumors of the urinary tract, prostate, testis, and adrenal glands.
6. Gynecologic Tumors
Table 5 summarizes the data reported in the following sections.
6.1. Ovary
Pan et al. reported increased DAXX expression across a wide spectrum of ovarian tumors, including cystadenomas, endometrioid carcinomas, clear cell carcinomas, and mucinous cystadenomas. On the contrary, granular cell tumor samples as well as normal ovary tissue specimens exhibited weak DAXX immunostaining [ 8 ]. In serous effusion specimens, DAXX expression in high-grade serous carcinoma cells was associated with poor patients’ OS [ 85 ]. On the other hand, in a study that included 187 epithelial ovarian cancer specimens, no statistically significant association between DAXX mRNA expression and clinicopathological parameters was observed [ 86 ].
HJURP immunoexpression in ovarian cancer cases has been investigated in two studies, both of which underlined its tumor-promoting properties. The first study reported an association between increased HJURP expression and high (≥200 U/mL) serum carbohydrate antigen 125 (CA125) levels, large (≥3000 mL) ascites volume, the presence of metastasis in the omentum/peritoneum, as well as shorter patients’ DFS and OS [ 87 ]. Li et al. also observed that high HJURP expression levels were linked to lymph node metastases and lower OS [ 88 ].
Therefore, both DAXX and HJURP are shown to participate in ovarian neoplastic processes ( Figure 2 ), with further implications for patients’ OS, as far as DAXX is concerned, and disease staging as well as for patients’ DFS and OS in the case of HJURP ( Figure 3 ).
6.2. Uterus
DAXX homozygous deletions were detected in 11% of endometrial clear cell carcinoma cases [ 89 ]. In leiomyosarcoma patients, loss of ATRX or DAXX expression was associated with lower DFS and lower OS [ 90 ], while only one case of cellular uterine leiomyoma (UL) exhibited the loss of DAXX expression [ 91 ].
Regarding HJURP expression, increased HJURP mRNA expression in endometrial carcinoma specimens was linked to high tumor grade, disease recurrence, and worse patients’ OS [ 92 ].
DAXX appears to play a protective role in uterine carcinogenesis ( Figure 2 ) with potential utility as a prognostic biomarker ( Figure 3 ). On the contrary, HJURP acts as a tumor-promoter in this specific organ ( Figure 2 ), with possible implications in disease diagnosis and prognosis ( Figure 3 ).
6.3. Cervix
In cervical neoplastic tissues, DAXX intracellular localization seems to be implicated in different stages of disease progression. DAXX IHC expression was located in the nucleus of normal cervical epithelial cells, in the nuclear membrane and, to a lesser extent, in the nucleus of cervical intraepithelial neoplasia grade 1 (CIN1) cells and in the cytoplasm and cell membrane in cervical intraepithelial neoplasia grade 2 (CIN2), CIN3, and cervical cancer cells [ 93 ]. It is possible that during the progress of cervical cancer, DAXX gradually translocates from the nucleus into the nuclear membrane, cytoplasm, and cell membrane. DAXX is eventually located in the cytoplasm and cell membrane in CIN2, CIN3, and cervical cancer cells.
As is the case for gastric cancer, DAXX intracellular location seems to constitute a key factor regarding its tumorigenic role in cervical cancer ( Figure 2 ).
7. Hematological Malignancies
Despite the quite extensive research conducted in the field of solid tumors, few studies investigate DAXX and HJURP expression and its clinical correlations in the setting of hematological malignancies. In this section, given the complexity of the classification of hematological neoplasms, we present them subdivided into main disease categories ( Table 6 ).
7.1. Acute Leukemias
For acute leukemias (ALs), most of the published research focuses on the pediatric population. Three Chinese studies investigated DAXX expression via IHC assays in pediatric ALs. Jingqiao et al. reported a statistically significant increased rate of DAXX protein expression in all leukemia subgroups studied, namely 30.38% for acute lymphoblastic leukemia (ALL), 66.67% for acute non-lymphocytic leukemia (ANLL), and 46.67% for acute myeloid leukemia (AML) compared to 6.67% for healthy controls [ 94 ]. In accordance with this, Liu et al. documented a significantly higher DAXX protein expression rate of 38% overall for pediatric ALs compared to a 5% rate for the control group, also highlighting that children diagnosed with ANLL had significantly higher DAXX expression levels (62.5%) than those diagnosed with ALL (26.5%). Analyzing the data based on the leukemia subtype, increased DAXX expression was statistically significant only for the ANLL group and not for the ALL compared to controls. Given this finding, the ALL group was further divided in two subgroups, high-risk (HR) ALL and standard-risk (SR) ALL. Interestingly, DAXX protein was expressed in 55.6% of the HR ALL subgroup, but it was not expressed in the SR ALL subgroup [ 95 ]. Taking a step further, Han-hua et al. investigated the possible correlation between DAXX and nuclear factor kappa B (NF-κB) expression in pediatric acute leukemias. For ALL, DAXX expression was positively correlated with NF-κB expression. HR ALL was characterized by higher expression rates of both DAXX and NF-κB (55.6% and 77.8%, respectively) compared to SR ALL (0.0% and 16.7%, respectively) [ 96 ].
Regarding adult acute leukemia, only one study by Ding et al., applying deep sequencing to detect somatic mutations, reported DAXX to be among novel, recurrently mutated genes in relapsed AML [ 97 ].
We can therefore conclude that DAXX exerts a possible tumor-promoting role of DAXX in the setting of pediatric AL, specifically ANLL and HR ALL ( Figure 2 ), and could serve as a prognostic marker for relapse in adult AML ( Figure 3 ).
7.2. Myelodysplastic Neoplasms
Attieh et al. evaluated bone marrow (BM) aspiration samples from 77 patients with myelodysplastic neoplasms (MDS) and identified that DAXX mRNA expression in MDS CD34+ cells, assessed by real-time PCR, was significantly upregulated compared to healthy controls. Nevertheless, upregulated DAXX mRNA expression levels did not significantly correlate either with WHO or cytogenetic subset or with patient outcome [ 98 ].
Hence, even though further research is undoubtedly required, based on this single published study regarding MDS, a possible protumorigenic role of DAXX could be proposed ( Figure 2 ).
7.3. Chronic Lymphocytic Leukemia
The only published report for DAXX protein expression in chronic lymphocytic leukemia (CLL) can be found in the study of Bojarska-Junak et al., where the authors documented a positive correlation between the expression of prostate apoptosis response-4 (Par-4) protein and DAXX protein, assessed via flow cytometry in peripheral blood and BM samples from patients with untreated CLL [ 99 ].
Given the correlation of Par-4 expression with adverse prognostic markers for CLL [ 99 ], we could assume an indirect association between DAXX expression and dismal CLL prognosis ( Figure 3 ), a remark definitely requiring validation.
7.4. Lymphomas
Hornviller et al. assessed via Western blot DAXX protein expression in purified B cells derived from cell suspensions of lymph nodes from patients with diffuse large B cell lymphoma (DLBCL), identifying increased expression in the DLBCL cases compared to B cells derived from tonsils. The researchers also applied tissue microarray analysis to assess DAXX expression in 196 DLBCL tissue samples so that they could make comparisons with other types of lymphoproliferative diseases and correlations with disease outcomes, given the large scale of the sample size. DAXX protein expression was significantly increased in DLBCL compared to follicular lymphoma (FL) and CLL. A Kaplan–Meier analysis showed that high DAXX expression correlated with poor OS for all subtypes of DLBCL [ 100 ].
For Natural Killer/T Cell Lymphoma (NKTCL), IHC staining demonstrated that the defined by transcriptomic analysis HEA subtype (based on HDAC9, EP300, and ARID1A mutations) was characterized by DAXX protein overexpression, in IHC analysis, proposing that DAXX could serve as a hallmark for this molecular subtype. Of note, DAXX was significantly correlated with NF-κB and T cell receptor (TCR) pathways [ 101 ].
Considering the multiple lymphoma subtypes, the reports for the two aforementioned studies are less than adequate to allow conclusions. We can though underline a possible tumor-promoting contribution of DAXX in DLBCL ( Figure 2 ), in the setting of which DAXX expression could be proposed as a new prognostic marker for the identification of patients with worse outcomes ( Figure 3 ). For the less frequent cases of NKTCL DAXX could serve as a marker for molecular subtype discrimination.
7.5. Multiple Myeloma
Jia et al. performed in silico analyses on publicly available Gene Expression Omnibus datasets ( GSE2113 and GSE6477 ), containing samples from patients with monoclonal gammopathy of undetermined significance (MGUS), multiple myeloma (MM), and plasma cell leukemia (PCL). A gradual increase in HJURP expression was observed along with disease progression from MGUS to PCL. Of note, relapsed MM cases demonstrated higher HJURP expression levels compared to non-relapsed. In the same study, a Kaplan–Meier analysis of several myeloma patient datasets (CoMMpass, HOVON, and UAMS) showed high HJURP value was associated with worse OS and progression-free survival (PFS) [ 102 ].
Thus, HJURP expression promotes disease progression in the setting plasma cell dyscrasias ( Figure 2 ), while it can also be used as a prognostic marker of patients’ outcome ( Figure 3 ).
8. Conclusions
Epigenetic modifications have been in the spotlight of cancer research in recent years, as a deeper understanding of their implication in tumorigenesis holds the key to early detection and precise diagnosis of tumors, the estimation of patients’ prognosis, and the development of novel, personalized, and ever more effective therapeutic interventions. DNA and RNA methylation mechanisms, histone modifications, and expression of non-coding RNAs constitute fundamental processes behind carcinogenesis and tumor-suppression [ 103 , 104 , 105 , 106 , 107 , 108 , 109 ]. Extensive research has emphasized the role of DAXX and HJURP, among other biomolecules implicated in epigenetic mechanisms, in the pathogenesis of a great variety of neoplasms. Their significance in crucial steps of carcinogenesis renders them potential biomarkers for timely disease diagnosis, assessment of patients’ prognosis, therapy monitoring as well as targets for the development of new, personalized treatment options. In PanNETs, DAXX is already routinely used as a trustworthy biomarker for the diagnosis of a well-differentiated neuroendocrine tumor as well as a predictor of a poor outcome. Researchers have revealed that ALT, driven by DAXX mutations, is the driving force behind PanNET neoplastic process, a mechanism separate from the molecular background of pancreatic neuroendocrine carcinoma tumorigenesis, which includes aberrations in the expression of p53 and retinoblastoma protein [ 110 ]. Apart from this established role in PanNet diagnosis and prognosis, a substantial amount of accumulating data highlight DAXX and HJURP as having either reliable tumor-promoting or tumor-suppressing properties and reveal their possible role as indicators of favorable or grim disease prognosis in various neoplastic diseases. More specifically, as presented in Table 1 , Table 2 , Table 3 , Table 4 , Table 5 and Table 6 , researchers have linked DAXX and HJURP with a multitude of clinicopathological parameters, depending on the tumor tissue of origin ( Figure 3 ).
Overall, an extensive review of the existing literature reveals an overwhelmingly adverse effect of DAXX and HJURP in carcinogenesis, with numerous harmful processes instigated by their overexpression in neoplastic cells. Ample data regarding the implication of the two biomolecules in tumors originating from the brain, lungs, esophagus, liver, prostate, and ovaries currently exist, with unequivocally damning evidence of their tumorigenic role. Therefore, it is becoming increasingly clear that DAXX and HJURP represent promising molecular targets of future anti-cancer medications, especially in the aforementioned organs of origin. For other types of neoplasms, such as those of the hematopoietic system, a limited number of studies support the protumorigenic role of DAXX and HJURP, rendering further investigations necessary to establish their function and possible application in the clinical setting. Nevertheless, aberrations in DAXX and HJURP expression are consistently linked to patients’ DFS and OS for cancers originating from the brain, lungs, breast, esophagus, liver, prostate, ovaries, the uterus. More studies are needed to help establish a stronger link between DAXX and HJURP expression and patients’ prognosis, in order for them to emerge as solid biomarkers of disease outcome. Lastly, as far as diagnosis is concerned, DAXX is already used for the identification of PanNETs. Few data exist designating them as useful for disease diagnosis, with further research needed to elucidate their potential role as trustworthy markers in that field.
The role of the tumor microenvironment in oncogenesis is increasingly in the epicenter of cancer research, as interplay between tumor cells and stromal elements is considered a defining factor for disease progression. Bravaccini et al. underlined that in in situ breast carcinoma cases, a greater than sevenfold risk of relapse was observed in patients highly expressing HJURP in stroma [ 29 ]. Moreover, immune reaction is emerging as a crucial element in carcinogenesis and especially patients’ prognosis. HJURP was highlighted as a regulator in this procedure in ccRCC specimens, with increased HJURP expression levels being associated with infiltration of different types of immune cells [ 75 ].
However, in many tumors, contradictory data have been reported regarding the properties of DAXX and HJURP in neoplasia. In CRC cases, different groups of researchers have attributed both tumor-suppressive [ 44 , 45 , 46 ] and tumor-promoting [ 47 ] properties to DAXX. Similarly, in ccRCC specimens, HJURP has been reported as having a negative [ 72 , 75 ], neutral [ 73 ], and protective [ 74 ] role in tumorigenesis. This can be attributed to the aberrant amplification of different molecular pathways leading to carcinogenesis. Each tumor carries a unique molecular signature, and a deeper understanding of it is a key step for the development of personalized therapeutic interventions. Nevertheless, such discrepancies render evident the need for further research to elucidate the complex role of DAXX and HJURP in carcinogenesis. Especially for tumors of the same histological type, where some research teams detected tumor-promoting and others tumor-suppressing properties of the aforementioned molecules, the investigation of their expression and its impact in large series of tumor samples is called for.
To summarize, an increasing amount of research in numerous types of neoplasia has underlined the implications of DAXX and HJURP in disease pathogenesis and has highlighted clinicopathological and prognostic correlations. Undoubtedly, additional studies are indispensable for the validation of these findings and for the establishment of these biomolecules as diagnostic and prognostic markers in cancer. Deciphering their intricate role in carcinogenesis will offer new therapeutic targets for personalized treatment approaches.
Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content.
Author Contributions
Writing—original draft preparation: A.P. and I.E.S.; investigation: A.P. and I.E.S.; data collection: A.P. and I.E.S.; visualization: A.P.; writing, review and editing: A.P., I.G., I.E.S. and S.P.P.; supervision: J.K. and S.T. All authors have read and agreed to the published version of the manuscript.
Institutional Review Board Statement
Not applicable.
Informed Consent Statement
Not applicable.
Data Availability Statement
Not applicable.
Conflicts of Interest
The authors declare no conflict of interest.
References
1. Global Cancer Observatory 2020 Available online: https://gco.iarc.fr/ (accessed on 1 May 2023)
2. Mahmud I. Liao D. DAXX in cancer: Phenomena, processes, mechanisms and regulation Nucleic Acids Res. 2019 47 7734 7752 10.1093/nar/gkz634 31350900 PMC6735914
3. Lewis P.W. Elsaesser S.J. Noh K.-M. Stadler S.C. Allis C.D. Daxx is an H3.3-specific histone chaperone and cooperates with ATRX in replication-independent chromatin assembly at telomeres Proc. Natl. Acad. Sci. USA 2010 107 14075 14080 10.1073/pnas.1008850107 20651253 PMC2922592
4. Yang X. Khosravi-Far R. Chang H.Y. Baltimore D. Daxx, a Novel Fas-Binding Protein That Activates JNK and Apoptosis Cell 1997 89 1067 1076 10.1016/S0092-8674(00)80294-9 9215629 PMC2989411
5. Shiizaki S. Naguro I. Ichijo H. Activation mechanisms of ASK1 in response to various stresses and its significance in intracellular signaling Adv. Biol. Regul. 2013 53 135 144 10.1016/j.jbior.2012.09.006 23031789
6. Obsilova V. Honzejkova K. Obsil T. Structural Insights Support Targeting ASK1 Kinase for Therapeutic Interventions Int. J. Mol. Sci. 2021 22 13395 10.3390/ijms222413395 34948191 PMC8705584
7. Nye J. Melters D.P. Dalal Y. The Art of War: Harnessing the epigenome against cancer F1000Research 2018 7 141 10.12688/f1000research.12833.1 29479426 PMC5801563
8. Pan W.-W. Zhou J.-J. Liu X.-M. Xu Y. Guo L.-J. Yu C. Shi Q.-H. Fan H.-Y. Death Domain-associated Protein DAXX Promotes Ovarian Cancer Development and Chemoresistance J. Biol. Chem. 2013 288 13620 13630 10.1074/jbc.M112.446369 23539629 PMC3650397
9. PubMed Available online: https://pubmed.ncbi.nlm.nih.gov/ (accessed on 1 October 2023)
10. Cavalcante S.G. Pereira B.J. Lerario A.M. Sola P.R. Oba-Shinjo S.M. Marie S.K. The chromatin remodeler complex ATRX-DAXX-H3.3 and telomere length in meningiomas Clin. Neurol. Neurosurg. 2021 210 106962 10.1016/j.clineuro.2021.106962 34624827
11. Cantero D. de Lope R. de la Presa R.M. Sepúlveda J.M. Borrás J.M. Castresana J.S. D’haene N. García J.F. Salmon I. Mollejo M. Molecular Study of Long-Term Survivors of Glioblastoma by Gene-Targeted Next-Generation Sequencing J. Neuropathol. Exp. Neurol. 2018 77 710 716 10.1093/jnen/nly048 30010995
12. Aksoy S.A. Mutlu M. Tunca B. Kocaeli H. Taskapilioglu M.O. Bekar A. Tekin C. Argadal O.G. Civan M.N. Kaya I.S. Coexistence of TERT C228T mutation and MALAT1 dysregulation in primary glioblastoma: New prognostic and therapeutic targets Neurol. Res. 2021 43 916 925 10.1080/01616412.2021.1948738 34210246
13. Kurihara S. Hiyama E. Onitake Y. Yamaoka E. Hiyama K. Clinical features of ATRX or DAXX mutated neuroblastoma J. Pediatr. Surg. 2014 49 1835 1838 10.1016/j.jpedsurg.2014.09.029 25487495
14. Heaphy C.M. Bi W.L. Coy S. Davis C. Gallia G.L. Santagata S. Rodriguez F.J. Telomere length alterations and ATRX/DAXX loss in pituitary adenomas Mod. Pathol. 2020 33 1475 1481 10.1038/s41379-020-0523-2 32203094 PMC8867890
15. de Tayrac M. Aubry M. Saïkali S. Etcheverry A. Surbled C. Guénot F. Galibert M.-D. Hamlat A. Lesimple T. Quillien V. A 4-Gene Signature Associated with Clinical Outcome in High-Grade Gliomas Clin. Cancer Res. 2011 17 317 327 10.1158/1078-0432.CCR-10-1126 21224364
16. de Tayrac M. Saikali S. Aubry M. Bellaud P. Boniface R. Quillien V. Mosser J. Prognostic Significance of EDN/RB, HJURP, p60/CAF-1 and PDLI4, Four New Markers in High-Grade Gliomas PLoS ONE 2013 8 e73332 10.1371/journal.pone.0073332 24039914 PMC3770632
17. Valente V. Serafim R.B. de Oliveira L.C. Adorni F.S. Torrieri R. Tirapelli D.P.d.C. Espreafico E.M. Oba-Shinjo S.M. Marie S.K.N. Paçó-Larson M.L. Modulation of HJURP (Holliday Junction-Recognizing Protein) Levels Is Correlated with Glioblastoma Cells Survival PLoS ONE 2013 8 e62200 10.1371/journal.pone.0062200 23638004 PMC3636219
18. Lin G.-J. Huang Y.-S. Lin C.-K. Huang S.-H. Shih H.-M. Sytwu H.-K. Chen Y.-W. Daxx and TCF4 interaction links to oral squamous cell carcinoma growth by promoting cell cycle progression via induction of cyclin D1 expression Clin. Oral Investig. 2016 20 533 540 10.1007/s00784-015-1536-y PMC4799237 26205068
19. Tsevegjav B. Takano A. Zhu M. Yoshitake Y. Shinohara M. Daigo Y. Holliday junction recognition protein as a prognostic biomarker and therapeutic target for oral cancer Int. J. Oncol. 2022 60 26 10.3892/ijo.2022.5316 35103286
20. Levidou G. Palamaris K. Sykaras A.G. Andreadakis G. Masaoutis C. Theochari I. Korkolopoulou P. Rontogianni D. Theocharis S. Unraveling the Role of Histone Variant CENP-A and Chaperone HJURP Expression in Thymic Epithelial Neoplasms Int. J. Mol. Sci. 2022 23 8339 10.3390/ijms23158339 35955489 PMC9368969
21. Ma J. Cai X. Kang L. Chen S. Liu H. Identification of novel biomarkers and candidate small-molecule drugs in cutaneous melanoma by comprehensive gene microarrays analysis J. Cancer 2021 12 1307 1317 10.7150/jca.49702 33531976 PMC7847648
22. Buentzel J. Yao S. Elakad O. Lois A.-M. Brünies J. König J. Hinterthaner M. Danner B.C. Ströbel P. Emmert A. Expression and prognostic impact of alpha thalassemia/mental retardation X-linked and death domain-associated protein in human lung cancer Medicine 2019 98 e16712 10.1097/MD.0000000000016712 31374064 PMC6708616
23. Yin Q. Chen W. Zhang C. Wei Z. A convolutional neural network model for survival prediction based on prognosis-related cascaded Wx feature selection Lab. Investig. 2022 102 1064 1074 10.1038/s41374-022-00801-y 35810236
24. Wang L. Qu J. Liang Y. Zhao D. Rehman F.U. Qin K. Zhang X. Identification and validation of key genes with prognostic value in non-small-cell lung cancer via integrated bioinformatics analysis Thorac. Cancer 2020 11 851 866 10.1111/1759-7714.13298 32059076 PMC7113067
25. Wei Y. Ouyang G.-L. Yao W.-X. Zhu Y.-J. Li X. Huang L.-X. Yang X.-W. Jiang W.-J. Knockdown of HJURP inhibits non-small cell lung cancer cell proliferation, migration, and invasion by repressing Wnt/beta-catenin signaling Eur. Rev. Med. Pharmacol. Sci. 2019 23 3847 3856 10.26355/eurrev_201905_17812 31115012
26. Chen L. Zeng C. Yan L. Liao W. Zhen C. Yao J. Prognostic value of Holliday junction-recognizing protein and its correlation with immune infiltrates in lung adenocarcinoma Oncol. Lett. 2022 24 232 10.3892/ol.2022.13353 35720487 PMC9185153
27. Hussien M.T. Shaban S. Temerik D.F. Helal S.R. Mosad E. Elgammal S. Mostafa A. Hassan E. Ibrahim A. Impact of DAXX and ATRX expression on telomere length and prognosis of breast cancer patients J. Egypt. Natl. Cancer Inst. 2020 32 34 10.1186/s43046-020-00045-1 PMC13317084 32856116
28. Yanai H. Ishida M. Yoshikawa K. Tsuta K. Sekimoto M. Sugie T. Immunohistochemical analyses of the expression profiles of INSM1, ATRX, DAXX and DLL3 in solid papillary carcinomas of the breast Oncol. Lett. 2022 23 137 10.3892/ol.2022.13257 35317025 PMC8907926
29. Bravaccini S. Tumedei M.M. Scarpi E. Zoli W. Rengucci C. Serra L. Curcio A. Buggi F. Folli S. Rocca A. New Biomarkers to Predict the Evolution of In Situ Breast Cancers BioMed Res. Int. 2014 2014 159765 10.1155/2014/159765 25243117 PMC4160633
30. Lehmann B.D. Bauer J.A. Chen X. Sanders M.E. Chakravarthy A.B. Shyr Y. Pietenpol J.A. Identification of human triple-negative breast cancer subtypes and preclinical models for selection of targeted therapies J. Clin. Investig. 2011 121 2750 2767 10.1172/JCI45014 21633166 PMC3127435
31. Milioli H.H. Tishchenko I. Riveros C. Berretta R. Moscato P. Basal-like breast cancer: Molecular profiles, clinical features and survival outcomes BMC Med. Genom. 2017 10 19 10.1186/s12920-017-0250-9 PMC5370447 28351365
32. Hu Z. Huang G. Sadanandam A. Gu S. Lenburg M.E. Pai M. Bayani N. Blakely E.A. Gray J.W. Mao J.-H. The expression level of HJURP has an independent prognostic impact and predicts the sensitivity to radiotherapy in breast cancer Breast Cancer Res. 2010 12 R18 10.1186/bcr2487 20211017 PMC2879562
33. de Oca R.M. Gurard-Levin Z.A. Berger F. Rehman H. Martel E. Corpet A. de Koning L. Vassias I. Wilson L.O. Meseure D. The histone chaperone HJURP is a new independent prognostic marker for luminal A breast carcinoma Mol. Oncol. 2015 9 657 674 10.1016/j.molonc.2014.11.002 25497280 PMC5528705
34. Panse G. Chrisinger J.S. Leung C.H. Ingram D.R. Khan S. Wani K. Lin H. Lazar A.J. Wang W. Clinicopathological analysis of ATRX, DAXX and NOTCH receptor expression in angiosarcomas Histopathology 2018 72 239 247 10.1111/his.13337 28796347
35. He L. Shi X. Chen R. Wu Z. Yang Z. Li Z. Association of Mental Health-Related Proteins DAXX, DRD3, and DISC1 with the Progression and Prognosis of Chondrosarcoma Front. Mol. Biosci. 2019 6 134 10.3389/fmolb.2019.00134 31850367 PMC6888811
36. Vargas A.C. Gray L.-A. White C.L. Maclean F.M. Grimison P. Ardakani N.M. Bonar F. Algar E.M. Cheah A.L. Russell P. Genome wide methylation profiling of selected matched soft tissue sarcomas identifies methylation changes in metastatic and recurrent disease Sci. Rep. 2021 11 667 10.1038/s41598-020-79648-6 33436720 PMC7804318
37. Liau J.-Y. Tsai J.-H. Jeng Y.-M. Lee J.-C. Hsu H.-H. Yang C.-Y. Leiomyosarcoma with Alternative Lengthening of Telomeres Is Associated with Aggressive Histologic Features, Loss of ATRX Expression, and Poor Clinical Outcome Am. J. Surg. Pathol. 2015 39 236 244 10.1097/PAS.0000000000000324 25229770
38. Akaike K. Toda-Ishii M. Suehara Y. Mukaihara K. Kubota D. Mitani K. Takagi T. Kaneko K. Yao T. Saito T. TERT promoter mutations are a rare event in gastrointestinal stromal tumors SpringerPlus 2015 4 836 10.1186/s40064-015-1606-2 26753123 PMC4695492
39. Wu H. Zhang B. Zhao J. Zhao Y. Ma X. Feng H. Weighted Gene Co-Expression Network Analysis Identifies Five Hub Genes Associated with Metastasis in Synovial Sarcoma Comb. Chem. High Throughput Screen. 2022 25 1767 1777 10.2174/1386207324666210628112429 34182903
40. Ko T.Y. Kim J.I. Park E.S. Mun J.M. Park S.D. The Clinical Implications of Death Domain-Associated Protein (DAXX) Expression Korean J. Thorac. Cardiovasc. Surg. 2018 51 187 194 10.5090/kjtcs.2018.51.3.187 29854663 PMC5973215
41. Yuen H.-F. Chan Y.-P. Law S. Srivastava G. El-Tanani M. Mak T.-W. Chan K.-W. DJ-1 Could Predict Worse Prognosis in Esophageal Squamous Cell Carcinoma Cancer Epidemiol. Biomark. Prev. 2008 17 3593 3602 10.1158/1055-9965.EPI-08-0214 19064576
42. Chen C. Sun X. Xie W. Chen S. Hu Y. Xing D. Xu J. Chen X. Zhao Z. Han Z. Opposing biological functions of the cytoplasm and nucleus DAXX modified by SUMO-2/3 in gastric cancer Cell Death Dis. 2020 11 514 10.1038/s41419-020-2718-3 32641734 PMC7343808
43. Xu J. Zhao Z. Ye L. Zhuge W. Han Z. Zhang T. Ye S. Chen W. Zhu S. Shi L. Prognostic significance of Daxx NCR (Nuclear/Cytoplasmic Ratio) in gastric cancer Cancer Med. 2017 6 2063 2075 10.1002/cam4.1144 28812328 PMC5603835
44. Chen Y.-C. Lee T.-H. Tzeng S.-L. Reduced DAXX Expression Is Associated with Reduced CD24 Expression in Colorectal Cancer Cells 2019 8 1242 10.3390/cells8101242 31614769 PMC6830082
45. Liu Y. Guo F. Zhu X. Guo W. Fu T. Wang W. Death Domain-Associated Protein Promotes Colon Cancer Metastasis through Direct Interaction with ZEB1 J. Cancer 2020 11 750 758 10.7150/jca.34233 31942198 PMC6959037
46. Tzeng S.-L. Cheng Y.-W. Li C.-H. Lin Y.-S. Hsu H.-C. Kang J.-J. Physiological and Functional Interactions between Tcf4 and Daxx in Colon Cancer Cells J. Biol. Chem. 2006 281 15405 15411 10.1074/jbc.M601807200 16569639
47. Huang Y.-S. Wu C.-C. Chang C.-C. Huang S.-F. Kuo H.-Y. Shih H.-M. Reciprocal regulation of Daxx and PIK3CA promotes colorectal cancer cell growth Cell. Mol. Life Sci. 2022 79 367 10.1007/s00018-022-04399-8 35718818 PMC11072676
48. Kang D.H. Woo J. Kim H. Kim S.Y. Ji S. Jaygal G. Ahn T.S. Kim H.J. Kwak H.J. Kim C.-J. Prognostic Relevance of HJURP Expression in Patients with Surgically Resected Colorectal Cancer Int. J. Mol. Sci. 2020 21 7928 10.3390/ijms21217928 33114545 PMC7662712
49. Li C. Ding J. Mei J. Comprehensive Analysis of Epigenetic Associated Genes on Differential Gene Expression and Prognosis in Hepatocellular Carcinoma J. Environ. Pathol. Toxicol. Oncol. 2022 41 27 43 10.1615/JEnvironPatholToxicolOncol.2021039641 35378002
50. Li Y. Yi Q. Liao X. Han C. Zheng L. Li H. Yu Q. Yan X. Chen X. Zhu H. Hypomethylation-driven overexpression of HJURP promotes progression of hepatocellular carcinoma and is associated with poor prognosis Biochem. Biophys. Res. Commun. 2021 566 67 74 10.1016/j.bbrc.2021.05.102 34119827
51. Hu B. Wang Q. Wang Y. Chen J. Li P. Han M. Holliday junction–recognizing protein promotes cell proliferation and correlates with unfavorable clinical outcome of hepatocellular carcinoma OncoTargets Ther. 2017 10 2601 2607 10.2147/OTT.S127738 PMC5440066 28553125
52. Yang Y. Yuan J. Liu Z. Cao W. Liu P. The expression, clinical relevance, and prognostic significance of HJURP in cholangiocarcinoma Front. Oncol. 2022 12 972550 10.3389/fonc.2022.972550 35965590 PMC9366246
53. Jiao Y. Shi C. Edil B.H. de Wilde R.F. Klimstra D.S. Maitra A. Schulick R.D. Tang L.H. Wolfgang C.L. Choti M.A. DAXX / ATRX , MEN1 , and mTOR Pathway Genes Are Frequently Altered in Pancreatic Neuroendocrine Tumors Science 2011 331 1199 1203 10.1126/science.1200609 21252315 PMC3144496
54. Hackeng W.M. Brosens L.A. Kim J.Y. O’Sullivan R. Sung Y.-N. Liu T.-C. Cao D. Heayn M. Brosnan-Cashman J. An S. Non-functional pancreatic neuroendocrine tumours: ATRX/DAXX and alternative lengthening of telomeres (ALT) are prognostically independent from ARX/PDX1 expression and tumour size Gut 2022 71 961 973 10.1136/gutjnl-2020-322595 33849943 PMC8511349
55. Ueda H. Akiyama Y. Shimada S. Mogushi K. Serizawa M. Matsumura S. Mitsunori Y. Aihara A. Ban D. Ochiai T. Tumor suppressor functions of DAXX through histone H3.3/H3K9me3 pathway in pancreatic NETs Endocr.-Relat. Cancer 2018 25 619 631 10.1530/ERC-17-0328 29599123
56. Venugopal A. Michalczyk A. Khasraw M. Ackland M.L. EMT Molecular Signatures of Pancreatic Neuroendocrine Neoplasms Int. J. Mol. Sci. 2022 23 13645 10.3390/ijms232113645 36362433 PMC9657865
57. Ziv E. Rice S.L. Filtes J. Yarmohammadi H. Boas F.E. Erinjeri J.P. Petre E.N. Brody L.A. Brown K.T. Covey A.M. Next generation sequencing of neuroendocrine tumors undergoing trans-arterial embolization reveals DAXX mutation status predicts shorter hepatic progression free survival and time to hepatic progression J. Vasc. Interv. Radiol. 2018 29 1519 1526 10.1016/j.jvir.2018.05.023 30342802 PMC7480743
58. Park J.K. Paik W.H. Lee K. Ryu J.K. Lee S.H. Kim Y.-T. DAXX/ATRX and MEN1 genes are strong prognostic markers in pancreatic neuroendocrine tumors Oncotarget 2017 8 49796 49806 10.18632/oncotarget.17964 28591701 PMC5564808
59. Marinoni I. Kurrer A.S. Vassella E. Dettmer M. Rudolph T. Banz V. Hunger F. Pasquinelli S. Speel E. Perren A. Loss of DAXX and ATRX Are Associated with Chromosome Instability and Reduced Survival of Patients with Pancreatic Neuroendocrine Tumors Gastroenterology 2014 146 453 460.e5 10.1053/j.gastro.2013.10.020 24148618
60. Pipinikas C.P. Dibra H. Karpathakis A. Feber A. Novelli M. Oukrif D. Fusai G. Valente R. Caplin M. Meyer T. Epigenetic dysregulation and poorer prognosis in DAXX-deficient pancreatic neuroendocrine tumours Endocr.-Relat. Cancer 2015 22 L13 L18 10.1530/ERC-15-0108 25900181 PMC4496774
61. Yuan F. Shi M. Ji J. Shi H. Zhou C. Yu Y. Liu B. Zhu Z. Zhang J. KRAS and DAXX/ATRX Gene Mutations Are Correlated with the Clinicopathological Features, Advanced Diseases, and Poor Prognosis in Chinese Patients with Pancreatic Neuroendocrine Tumors Int. J. Biol. Sci. 2014 10 957 965 10.7150/ijbs.9773 25210493 PMC4159686
62. Weisbrod A.B. Zhang L. Jain M. Barak S. Quezado M.M. Kebebew E. Altered PTEN, ATRX, CHGA, CHGB, and TP53 Expression Are Associated with Aggressive VHL-Associated Pancreatic Neuroendocrine Tumors Horm. Cancer 2013 4 165 175 10.1007/s12672-013-0134-1 23361940 PMC3644020
63. Sato S. Tsuchikawa T. Nakamura T. Sato N. Tamoto E. Okamura K. Shichinohe T. Hirano S. Impact of the tumor microenvironment in predicting postoperative hepatic recurrence of pancreatic neuroendocrine tumors Oncol. Rep. 2014 32 2753 2759 10.3892/or.2014.3530 25310565
64. Pea A. Yu J. Marchionni L. Noe M. Luchini C. Pulvirenti A. de Wilde R.F. Brosens L.A. Rezaee N. Javed A. Genetic Analysis of Small Well-differentiated Pancreatic Neuroendocrine Tumors Identifies Subgroups with Differing Risks of Liver Metastases Ann. Surg. 2020 271 566 573 10.1097/SLA.0000000000003022 30339629 PMC6565500
65. Kim J.Y. Brosnan-Cashman J.A. An S. Kim S.J. Song K.-B. Kim M.-S. Kim M.-J. Hwang D.W. Meeker A.K. Yu E. Alternative Lengthening of Telomeres in Primary Pancreatic Neuroendocrine Tumors Is Associated with Aggressive Clinical Behavior and Poor Survival Clin. Cancer Res. 2017 23 1598 1606 10.1158/1078-0432.CCR-16-1147 27663587 PMC5354973
66. Uemura J. Okano K. Oshima M. Suto H. Ando Y. Kumamoto K. Kadota K. Ichihara S. Kokudo Y. Maeba T. Immunohistochemically Detected Expression of ATRX, TSC2, and PTEN Predicts Clinical Outcomes in Patients with Grade 1 and 2 Pancreatic Neuroendocrine Tumors Ann. Surg. 2021 274 e949 e956 10.1097/SLA.0000000000003624 31599805
67. Chou A. Itchins M. de Reuver P.R. Arena J. Clarkson A. Sheen A. Sioson L. Cheung V. Perren A. Nahm C. ATRX loss is an independent predictor of poor survival in pancreatic neuroendocrine tumors Hum. Pathol. 2018 82 249 257 10.1016/j.humpath.2018.07.032 30081149
68. Yadav R. Kakkar A. Sharma A. Malik P.S. Sharma M.C. Study of clinicopathological features, hormone immunoexpression, and loss of ATRX and DAXX expression in pancreatic neuroendocrine tumors Scand. J. Gastroenterol. 2016 51 994 999 10.3109/00365521.2016.1170195 27162024
69. Chen S.-F. Kasajima A. Yazdani S. Chan M.S. Wang L. He Y.-Y. Gao H.-W. Sasano H. Clinicopathologic significance of immunostaining of α-thalassemia/mental retardation syndrome X-linked protein and death domain–associated protein in neuroendocrine tumors Hum. Pathol. 2013 44 2199 2203 10.1016/j.humpath.2013.04.025 23954140
70. Wang C.-J. Li X. Shi P. Ding H.-Y. Liu Y.-P. Li T. Lin P.-P. Wang Y.-S. Zhang G.-Q. Cao Y. Holliday junction recognition protein promotes pancreatic cancer growth and metastasis via modulation of the MDM2/p53 signaling Cell Death Dis. 2020 11 386 10.1038/s41419-020-2595-9 32439850 PMC7242411
71. Pivovarcikova K. Agaimy A. Martinek P. Alaghehbandan R. Perez-Montiel D. Alvarado-Cabrero I. Rogala J. Kuroda N. Rychly B. Gasparov S. Primary renal well-differentiated neuroendocrine tumour (carcinoid): Next-generation sequencing study of 11 cases Histopathology 2019 75 104 117 10.1111/his.13856 30851202
72. Wei W. Lv Y. Gan Z. Zhang Y. Han X. Xu Z. Identification of key genes involved in the metastasis of clear cell renal cell carcinoma Oncol. Lett. 2019 17 4321 4328 10.3892/ol.2019.10130 30988807 PMC6447949
73. Xu T. Ruan H. Gao S. Liu J. Liu Y. Song Z. Cao Q. Wang K. Bao L. Liu D. ISG20 serves as a potential biomarker and drives tumor progression in clear cell renal cell carcinoma Aging 2020 12 1808 1827 10.18632/aging.102714 32003757 PMC7053611
74. Yuan J. Chen Z. Wang K. Zhang Z. Holliday junction-recognition protein modulates apoptosis, cell cycle arrest and reactive oxygen species stress in human renal cell carcinoma Oncol. Rep. 2020 44 1246 1254 10.3892/or.2020.7656 32582972
75. Zhang F. Yuan D. Song J. Chen W. Wang W. Zhu G. Hu B. Chen X. Zhu J. HJURP is a prognostic biomarker for clear cell renal cell carcinoma and is linked to immune infiltration Int. Immunopharmacol. 2021 99 107899 10.1016/j.intimp.2021.107899 34217993
76. Zizzi A. Montironi M.A. Mazzucchelli R. Scarpelli M. Lopez-Beltran A. Cheng L. Paone N. Castellini P. Montironi R. Immunohistochemical analysis of chromatin remodeler DAXX in high grade urothelial carcinoma Diagn. Pathol. 2013 8 111 10.1186/1746-1596-8-111 23819605 PMC3751668
77. Burgess E.F. Sanders J.A. Livasy C. Symanowski J. Gatalica Z. Steuerwald N.M. Arguello D. Brouwer C.R. Korn W.M. Grigg C.M. Identification of potential biomarkers and novel therapeutic targets through genomic analysis of small cell bladder carcinoma and associated clinical outcomes Urol. Oncol. Semin. Orig. Investig. 2022 40 383.e1 383.e10 10.1016/j.urolonc.2022.04.019 35662501
78. Kwan P.S. Lau C.C. Chiu Y.T. Man C. Liu J. Tang K.D. Wong Y.C. Ling M.-T. Daxx regulates mitotic progression and prostate cancer predisposition Carcinogenesis 2012 34 750 759 10.1093/carcin/bgs391 23239745
79. Jamali L. Moradi A. Ganji M. Ayati M. Kazeminezhad B. Attar Z.F. Ghaedi H. Ghaderian S.M.H. Fallah-Karkan M. Ranjbar A. Potential Prognostic Role for SPOP, DAXX, RARRES1, and LAMP2 as an Autophagy Related Genes in Prostate Cancer Urol. J. 2020 17 156 163 10.22037/uj.v0i0.4935 30882175
80. Tsourlakis M.C. Schoop M. Plass C. Huland H. Graefen M. Steuber T. Schlomm T. Simon R. Sauter G. Sirma H. Overexpression of the chromatin remodeler death-domain–associated protein in prostate cancer is an independent predictor of early prostate-specific antigen recurrence Hum. Pathol. 2013 44 1789 1796 10.1016/j.humpath.2013.01.022 23642739
81. Puto L.A. Brognard J. Hunter T. Transcriptional Repressor DAXX Promotes Prostate Cancer Tumorigenicity via Suppression of Autophagy J. Biol. Chem. 2015 290 15406 15420 10.1074/jbc.M115.658765 25903140 PMC4505457
82. Chen Y. Liang Y. Yang J. Yuan D. Li J. Zheng S. Wan Y. Wang B. Han Z. Zhong W. Upregulation of Holliday junction recognition protein predicts poor prognosis and biochemical recurrence in patients with prostate cancer Oncol. Lett. 2019 18 6697 6703 10.3892/ol.2019.11061 31814851 PMC6888104
83. Luo C. Chen J. Chen L. Exploration of gene expression profiles and immune microenvironment between high and low tumor mutation burden groups in prostate cancer Int. Immunopharmacol. 2020 86 106709 10.1016/j.intimp.2020.106709 32593155
84. Mete O. Gucer H. Kefeli M. Asa S.L. Diagnostic and Prognostic Biomarkers of Adrenal Cortical Carcinoma Am. J. Surg. Pathol. 2018 42 201 213 10.1097/PAS.0000000000000943 28877067
85. Davidson B. McFadden E. Holth A. Brunetti M. Flørenes V.A. Death domain-associated protein (DAXX) expression is associated with poor survival in metastatic high-grade serous carcinoma Virchows Arch. 2020 477 857 864 10.1007/s00428-020-02842-4 32533344 PMC7683463
86. Pontikakis S. Papadaki C. Tzardi M. Trypaki M. Sfakianaki M. Koinis F. Lagoudaki E. Giannikaki L. Kalykaki A. Kontopodis E. Predictive value of ATP7b, BRCA1, BRCA2, PARP1, UIMC1 (RAP80), HOXA9, DAXX, TXN (TRX1), THBS1 (TSP1) and PRR13 (TXR1) genes in patients with epithelial ovarian cancer who received platinum-taxane first-line therapy Pharmacogenom. J. 2017 17 506 514 10.1038/tpj.2016.63 27779244
87. Dou Z. Qiu C. Zhang X. Yao S. Zhao C. Wang Z. Chu R. Chen J. Chen Z. Li R. HJURP Promotes Malignant Progression and Mediates Sensitivity to Cisplatin and WEE1-inhibitor in Serous Ovarian Cancer Int. J. Biol. Sci. 2022 18 1188 1210 10.7150/ijbs.65589 35173547 PMC8771849
88. Li L. Li X. Meng Q. Khan A.Q. Chen X. Increased Expression of Holliday Junction-Recognizing Protein (HJURP) as an Independent Prognostic Biomarker in Advanced-Stage Serous Ovarian Carcinoma Experiment 2018 24 3050 3055 10.12659/MSM.906647 29743473 PMC5970546
89. DeLair D.F. Burke K.A. Selenica P. Lim R.S. Scott S.N. Middha S. Mohanty A.S. Cheng D.T. Berger M.F. Soslow R.A. The genetic landscape of endometrial clear cell carcinomas J. Pathol. 2017 243 230 241 10.1002/path.4947 28718916 PMC5708127
90. Slatter T.L. Hsia H. Samaranayaka A. Sykes P. Clow W. Devenish C.J. Sutton T. Royds J.A. Pc P. Cheung A.N. Loss of ATRX and DAXX expression identifies poor prognosis for smooth muscle tumours of uncertain malignant potential and early stage uterine leiomyosarcoma J. Pathol. Clin. Res. 2015 1 95 105 10.1002/cjp2.11 27499896 PMC4858134
91. Ahvenainen T.V. Mäkinen N. Von Nandelstadh P. Vahteristo M.E. Pasanen A.M. Bützow R.C. Vahteristo P.M. Loss of ATRX/DAXX expression and alternative lengthening of telomeres in uterine leiomyomas Cancer 2018 124 4650 4656 10.1002/cncr.31754 30423196
92. Lv S. Xu X. Wu Z. Identification of key candidate genes and pathways in endometrial cancer: Evidence from bioinformatics analysis Oncol. Lett. 2019 18 6679 6689 10.3892/ol.2019.11040 31807178 PMC6876294
93. Tang S.-Y. Li L. Li Y.-L. Liu A.-Y. Yu M.-J. Wan Y.-P. Distribution and location of Daxx in cervical epithelial cells with high risk human papillomavirus positive Diagn. Pathol. 2014 9 1 10.1186/1746-1596-9-1 24398161 PMC3933295
94. Jingqiao F. Expression significance of Daxx protein in bone marrow cells of children with acute leukemia Chin. Pediatr. Integr. Tradit. West. Med. 2016 8 161 163 10.3969/j.issn.1674-3865.2016.02.011
95. Liu J. Zhang L.-Q. Hu Q. Lin H.-H. Liu A.-G. Tao H.-F. Song Y.-Q. Zhang X.-L. Expression of Daxx in children with acute leukemia Zhongguo dang dai er ke za zhi = Chin. J. Contemp. Pediatr. 2007 9 33 36 17306074
96. Han-hua L. Jing L. Liu-qing Z. Expression of Daxx in pediatric acute leukemia and its relationship with expression of NF-κB Chin. J. Pract. Pediatr. 2007 22 459 461
97. Ding L. Ley T.J. Larson D.E. Miller C.A. Koboldt D.C. Welch J.S. Ritchey J.K. Young M.A. Lamprecht T. McLellan M.D. Clonal evolution in relapsed acute myeloid leukaemia revealed by whole-genome sequencing Nature 2012 481 506 510 10.1038/nature10738 22237025 PMC3267864
98. Attieh Y. Geng Q.-R. DiNardo C.D. Zheng H. Jia Y. Fang Z.-H. Gañán-Gómez I. Yang H. Wei Y. Kantarjian H. Low frequency of H3.3 mutations and upregulated DAXX expression in MDS Blood 2013 121 4009 4011 10.1182/blood-2012-11-466714 23660862
99. Bojarska-Junak A. Sieklucka M. Hus I. Wąsik-Szczepanek E. Kusz M.L. Surdacka A. Chocholska S. Dmoszyńska A. Roliński J. Assessment of the pathway of apoptosis involving PAR-4, DAXX and ZIPK proteins in CLL patients and its relationship with the principal prognostic factors Folia Histochem. Cytobiol. 2011 49 98 103 10.5603/FHC.2011.0014 21526495
100. Horvilleur E. Sbarrato T. Hill K. Spriggs R.V. Screen M. Goodrem P.J. Sawicka K. Chaplin L.C. Touriol C. Packham G. A role for eukaryotic initiation factor 4B overexpression in the pathogenesis of diffuse large B-cell lymphoma Leukemia 2014 28 1092 1102 10.1038/leu.2013.295 24135829 PMC4017261
101. Xiong J. Cui B.-W. Wang N. Dai Y.-T. Zhang H. Wang C.-F. Zhong H.-J. Cheng S. Ou-Yang B.-S. Hu Y. Genomic and Transcriptomic Characterization of Natural Killer T Cell Lymphoma Cancer Cell 2020 37 403 419.e6 10.1016/j.ccell.2020.02.005 32183952
102. Jia Y. Zhou J. Tan T.K. Chung T.-H. Chen Y. Chooi J.-Y. Sanda T. Fullwood M.J. Xiong S. Toh S.H. Super Enhancer-Mediated Upregulation of HJURP Promotes Growth and Survival of t(4;14)-Positive Multiple Myeloma Cancer Res. 2022 82 406 418 10.1158/0008-5472.CAN-21-0921 34893510 PMC9397631
103. Sharma S. Kelly T.K. Jones P.A. Epigenetics in cancer Carcinogenesis 2010 31 27 36 10.1093/carcin/bgp220 19752007 PMC2802667
104. Lee J.E. Kim M.-Y. Cancer epigenetics: Past, present and future Semin. Cancer Biol. 2022 83 4 14 10.1016/j.semcancer.2021.03.025 33798724
105. Kanwal R. Gupta K. Gupta S. Cancer Epigenetics: An Introduction Methods in Molecular Biology Verma M. Springer New York, NY, USA 2015 Volume 1238 3 25 10.1007/978-1-4939-1804-1_1 25421652
106. Dawson M.A. Kouzarides T. Cancer Epigenetics: From Mechanism to Therapy Cell 2012 150 12 27 10.1016/j.cell.2012.06.013 22770212
107. Cheng Y. He C. Wang M. Ma X. Mo F. Yang S. Han J. Wei X. Targeting epigenetic regulators for cancer therapy: Mechanisms and advances in clinical trials Signal Transduct. Target. Ther. 2019 4 62 10.1038/s41392-019-0095-0 31871779 PMC6915746
108. Psilopatis I. Garmpis N. Garmpi A. Vrettou K. Sarantis P. Koustas E. Antoniou E.A. Dimitroulis D. Kouraklis G. Karamouzis M.V. The Emerging Role of Histone Deacetylase Inhibitors in Cervical Cancer Therapy Cancers 2023 15 2222 10.3390/cancers15082222 37190151 PMC10137219
109. Psilopatis I. Pergaris A. Vrettou K. Theocharis S. Troungos C. Thymic Epithelial Neoplasms: Focusing on the Epigenetic Alterations Int. J. Mol. Sci. 2022 23 4045 10.3390/ijms23074045 35409405 PMC8999627
110. Luchini C. Scarpa A. Neoplastic Progression in Neuroendocrine Neoplasms of the Pancreas Arch. Pathol. Lab. Med. 2023 10.5858/arpa.2022-0417-RA 36881771