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Rejuvenation Strategy for Inducing and Enhancing Autoimmune Response to Eliminate Senescent Cells.

The process of aging, which involves progressive changes in the body over time, is closely associated with the development of age-related diseases. Cellular senescence is a pivotal hallmark and mechanism of the aging process. The accumulation of senescent cells can significantly contribute to the onset of age-related diseases, thereby compromising overall health. Conversely, the elimination of senescent cells enhances the body's regenerative and reparative capacity, thereby retarding the aging process. Here, we present a brief overview of 12 Hallmarks of aging and subsequently emphasize the po

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… Epigenetic changes include modifications in DNA methylation patterns, aberrant histone modifications, loss of heterochromatin, reorganized three-dimensional (3D) genomic structures, and dysregulated RNA modifications [ 22 ]. …

LAP2α drives breast tumorigenesis by mitigating replication stress.

Replication protein A (RPA) plays a vital role in replication stress response, with RPA-coated single-stranded DNA (ssDNA) acting as a critical platform for the coordination of the genome surveillance machinery. In previous studies, we reported that the lamin-associated protein LAP2α interacts physically with RPA, aiding its localization to damaged chromatin for genome protection. However, the significance of the LAP2α-mediated RPA deposition in tumor progression remains unclear. Here, we reveal that LAP2α promotes breast tumorigenesis by counteracting replication stress-induced DNA damage. Fu

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… LAP2α orchestrates alternative lengthening of telomeres suppression through telomeric heterochromatin regulation with HDAC1: unveiling a potential therapeutic target. Cell Death Dis. 2024;15:761. 33. Bártová E, Legartová S, Krejčí J, Řezníčková P, Kovaříková AS, Suchánková J, et al. …

Looking for the Holy Grail-Drug Candidates for Glioblastoma Multiforme Chemotherapy.

Glioblastoma multiforme (GBM) is the deadliest and the most heterogeneous brain cancer. The median survival time of GBM patients is approximately 8 to 15 months after initial diagnosis. GBM development is determined by numerous signaling pathways and is considered one of the most challenging and complicated-to-treat cancer types. Standard GBM therapy consist of surgery followed by radiotherapy or chemotherapy, and combined treatment. Current standard of care (SOC) does not offer a significant chance for GBM patients to combat cancer, and the selection of available drugs is limited. For almost

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… On the other hand, deacetylation leads to condensed heterochromatin formation with a suppressed transcription process. …

Lysine Methyltransferase Inhibitors Impair H4K20me2 and 53BP1 Foci in Response to DNA Damage in Sarcomas, a Synthetic Lethality Strategy.

BackgroundChromatin is dynamically remodeled to adapt to all DNA-related processes, including DNA damage responses (DDR). This adaptation requires DNA and histone epigenetic modifications, which are mediated by several types of enzymes; among them are lysine methyltransferases (KMTs).MethodsKMT inhibitors, chaetocin and tazemetostat (TZM), were used to study their role in the DDR induced by ionizing radiation or doxorubicin in two human sarcoma cells lines. The effect of these KMT inhibitors was tested by the analysis of chromatin epigenetic modifications, H4K16ac and H4K20me2. DDR was monitor

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… Histone methylation is one of the most prevalent chromatin modifications and plays a key role in the regulation, activation and silencing of genes in euchromatin, and is also associated with heterochromatin condensation ( Dawson and Kouzarides, 2012 ). …

Hepatocellular carcinoma: Understanding molecular mechanisms for defining potential clinical modalities.

Liver cancer is the sixth most commonly occurring cancer and costs millions of lives per year. The diagnosis of hepatocellular carcinoma (HCC) has relied on scanning techniques and serum-based markers such as α-fetoprotein. These measures have limitations due to their detection limits and asymptomatic conditions during the early stages, resulting in late-stage cancer diagnosis where targeted chemotherapy or systemic treatment with sorafenib is offered. However, the aid of conventional therapy for patients in the advanced stage of HCC has limited outcomes. Thus, it is essential to seek a new tr

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… In HCC and gastric cancer, the inactive or suppressed state of tumor suppressor genes (TSGs) is mainly attributed to the overexpression of DNMTs and HDACs, leading to heterochromatinization. …

Molecular and epigenetic regulatory mechanisms of normal stem cell radiosensitivity.

Ionizing radiation (IR) therapy is a major cancer treatment modality and an indispensable auxiliary treatment for primary and metastatic cancers, but invariably results in debilitating organ dysfunctions. IR-induced depletion of neural stem/progenitor cells in the subgranular zone of the dentate gyrus in the hippocampus where neurogenesis occurs is considered largely responsible for deficiencies such as learning, memory, and spatial information processing in patients subjected to cranial irradiation. Similarly, IR therapy-induced intestinal injuries such as diarrhea and malabsorption are commo

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… Tsouroula K Temporal and spatial uncoupling of DNA double strand break repair pathways within mammalian heterochromatin Mol. Cell 2016 63 293 305 10.1016/j.molcel.2016.06.002 27397684 4. Campisi J d'Adda di Fagagna F Cellular senescence: when bad things happen to good cells Nat. Rev. Mol. …

Epigenetic treatment of pancreatic cancer: is there a therapeutic perspective on the horizon?

Pancreatic ductal adenocarcinoma (PDAC) constitutes one of the most aggressive malignancies with a 5-year survival rate of <7%. Due to growing incidence, late diagnosis and insufficient treatment options, PDAC is predicted to soon become one of the leading causes of cancer-related death. Although intensified cytostatic combinations, particularly gemcitabine plus nab-paclitaxel and the folinic acid, fluorouracil, irinotecan, oxaliplatin (FOLFIRINOX) protocol, provide some improvement in efficacy and survival compared with gemcitabine alone, a breakthrough in the treatment of metastatic pancreat

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… The switch between condensed and transcriptional inactive heterochromatin (left panel) and open, accessible euchromatin (right panel) is controlled by chromatin regulators that establish (‘writers’), maintain (‘readers’) or remove (‘erasers’) post-translational modifications on the lysine residues of …

Recent advances in tumor immunotherapy based on NK cells.

Immunotherapy has emerged as the established fourth pillar of cancer treatment following surgery, radiotherapy, and chemotherapy, representing a cutting-edge research domain in translational medicine and clinical oncology. Natural killer (NK) cells, a type of innate cytotoxic lymphocyte, possess unique antitumor properties that are independent of major histocompatibility complex (MHC) restrictions, making them promising candidates for "off-the-shelf" therapeutic products. NK cells can eliminate tumor cells through various mechanisms. Genetic engineering of NK cells can enhance their activation

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… TALEN outperforms Cas9 in editing heterochromatin target sites. Nat Commun. (2021) 12:606. doi: 10.1038/s41467-020-20672-5, PMID: 110. Kerbauy LN, Marin ND, Kaplan M, Banerjee PP, Berrien-Elliott MM, Becker-Hapak M, et al. …

Proteasome inhibition by bortezomib parallels a reduction in head and neck cancer cells growth, and an increase in tumor-infiltrating immune cells.

Head and neck cancer (HNC) has frequently an aggressive course for the development of resistance to standard chemotherapy. Thus, the use of innovative therapeutic drugs is being assessed. Bortezomib is a proteasome inhibitor with anticancer effects. In vitro antitumoral activity of Bortezomib was investigated employing human tongue (SCC-15, CAL-27), pharynx (FaDu), salivary gland (A-253) cancer cell lines and a murine cell line (SALTO-5) originated from a salivary gland adenocarcinoma arising in BALB-neuT male mice transgenic for the oncogene neu. Bortezomib inhibited cell proliferation, trigg

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… The nuclei appeared large, mainly formed by euchromatin with low dense heterochromatin in the periphery. In the cytoplasm several mitochondria and cisterns of rough endoplasmic reticulum were detected, with few vacuoles (Supplementary Fig. S7a,b). …

Prominent Role of Histone Modifications in the Regulation of Tumor Metastasis.

Tumor aggressiveness and progression is highly dependent on the process of metastasis, regulated by the coordinated interplay of genetic and epigenetic mechanisms. Metastasis involves several steps of epithelial to mesenchymal transition (EMT), anoikis resistance, intra- and extravasation, and new tissue colonization. EMT is considered as the most critical process allowing cancer cells to switch their epithelial characteristics and acquire mesenchymal properties. Emerging evidence demonstrates that epigenetics mechanisms, DNA methylation, histone modifications, and non-coding RNAs participate

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… Additionally, H3K9me3 in the Tripartite Motif Containing 33 (TRIM33)-Smad2/3 complex displaces the heterochromatin protein 1 (HP1), allowing the subsequent activation of mesendoderm differentiation genes, such as Goosecoid Homeobox ( GSC ) and Mix Paired-Like Homeobox ( MIXL1 ) [ 76 , 77 ]. …

Cancer Stem Cells: The Potential Targets of Chinese Medicines and Their Active Compounds.

The pivotal role of cancer stem cells (CSCs) in the initiation and progression of malignancies has been rigorously validated, and the specific methods for identifying and isolating the CSCs from the parental cancer population have also been rapidly developed in recent years. This review aims to provide an overview of recent research progress of Chinese medicines (CMs) and their active compounds in inhibiting tumor progression by targeting CSCs. A great deal of CMs and their active compounds, such as Antrodia camphorate, berberine, resveratrol, and curcumin have been shown to regress CSCs, in t

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… The effects of histone deacetylase inhibitors on heterochromatin: Implications for anticancer therapy? EMBO Rep. 2005;6:520–524. doi: 10.1038/sj.embor.7400441. 68. Butler L.M., Zhou X., Xu W.S., Scher H.I., Rifkind R.A., Marks P.A., Richon V.M. …

Epigenetics-targeted drugs: current paradigms and future challenges.

Epigenetics governs a chromatin state regulatory system through five key mechanisms: DNA modification, histone modification, RNA modification, chromatin remodeling, and non-coding RNA regulation. These mechanisms and their associated enzymes convey genetic information independently of DNA base sequences, playing essential roles in organismal development and homeostasis. Conversely, disruptions in epigenetic landscapes critically influence the pathogenesis of various human diseases. This understanding has laid a robust theoretical groundwork for developing drugs that target epigenetics-modifyin

Targeting Cellular Senescence in Aging and Age-Related Diseases: Challenges, Considerations, and the Emerging Role of Senolytic and Senomorphic Therapies.

Cellular senescence is characterized by the permanent arrest of cell proliferation and is a response to endogenous and exogenous stress. The continuous accumulation of senescent cells (SnCs) in the body leads to the development of aging and age-related diseases (such as neurodegenerative diseases, cancer, metabolic diseases, cardiovascular diseases, and osteoarthritis). In the face of the growing challenge of aging and age-related diseases, several compounds have received widespread attention for their potential to target SnCs. As a result, senolytics (compounds that selectively eliminate SnCs

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… Through histological analysis of the liver tissues of young and old cynophagous monkeys, researchers found that the livers of old monkeys showed aging phenotypes such as increased SnCs, elevated inflammatory factors, increased fibrosis, lipid deposition, and decreased heterochromatin [ 131 ]. … SIRT6 has multiple molecular functions, including DNA repair and heterochromatin regulation, which makes it a hub for regulating genomic and epigenome stability. …

Engagement of Mesenchymal Stromal Cells in the Remodeling of the Bone Marrow Microenvironment in Hematological Cancers.

Mesenchymal stromal cells (MSCs) are a subset of heterogeneous, non-hematopoietic fibroblast-like cells which play important roles in tissue repair, inflammation, and immune modulation. MSCs residing in the bone marrow microenvironment (BMME) functionally interact with hematopoietic stem progenitor cells regulating hematopoiesis. However, MSCs have also emerged in recent years as key regulators of the tumor microenvironment. Indeed, they are now considered active players in the pathophysiology of hematologic malignancies rather than passive bystanders in the hematopoietic microenvironment. Onc

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… Heterochromatin disorganization is a driver of MSC senescence [ 104 ]. AML-MSCs downregulate chromatin remodeling complex CHD1 (modulating chromatin condensation), the reduction of which is associated with a decrease in HSPCs’ supportive capacity [ 105 ]. …

The DNA methylation landscape of multiple myeloma shows extensive inter- and intrapatient heterogeneity that fuels transcriptomic variability.

BackgroundCancer evolution depends on epigenetic and genetic diversity. Historically, in multiple myeloma (MM), subclonal diversity and tumor evolution have been investigated mostly from a genetic perspective.MethodsHere, we performed an analysis of 42 MM samples from 21 patients by using enhanced reduced representation bisulfite sequencing (eRRBS). We combined several metrics of epigenetic heterogeneity to analyze DNA methylation heterogeneity in MM patients.ResultsWe show that MM is characterized by the continuous accumulation of stochastic methylation at the promoters of development-related

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… H3K27me3 redistribution could also play an important role in chromatin decompaction, as has been shown in ESCs [ 92 ], and could explain the increase in open chromatin regions within the heterochromatin state of MM samples [ 93 ]. …

Overcoming Antigen Escape and T-Cell Exhaustion in CAR-T Therapy for Leukemia.

Leukemia is a prevalent pediatric cancer with significant challenges, particularly in relapsed or refractory cases. Chimeric antigen receptor T-cell (CAR-T) therapy has emerged as a personalized cancer treatment, modifying patients' T cells to target and destroy resistant cancer cells. This study reviews the current therapeutic options of CAR-T therapy for leukemia, addressing the primary obstacles such as antigen escape and T-cell exhaustion. We explore dual-targeting strategies and their potential to improve treatment outcomes by preventing the loss of target antigens. Additionally, we exami

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… Furthermore, the alteration of SUV39H1—a histone 3 lysine 9 methyltransferase that facilitates the formation of heterochromatin—in human CAR-Ts resulted in the reprogramming of the CAR-T phenotype, which maintained its antitumor function [ 97 ]. …

Transcriptome Analysis Reveals Altered Inflammatory Pathway in an Inducible Glial Cell Model of Myotonic Dystrophy Type 1.

Myotonic dystrophy type 1 (DM1), the most frequent inherited muscular dystrophy in adults, is caused by the CTG repeat expansion in the 3'UTR of the DMPK gene. Mutant DMPK RNA accumulates in nuclear foci altering diverse cellular functions including alternative splicing regulation. DM1 is a multisystemic condition, with debilitating central nervous system alterations. Although a defective neuroglia communication has been described as a contributor of the brain pathology in DM1, the specific cellular and molecular events potentially affected in glia cells have not been totally recognized. Thus,

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… Antisense transcription and heterochromatin at the DM1 CTG repeats are constrained by CTCF. Mol. Cell. 2005;20:483–489. doi: 10.1016/j.molcel.2005.09.002. 22. Nguyen L., Cleary J.D., Ranum L.P.W. Repeat-Associated Non-ATG Translation: Molecular Mechanisms and Contribution to Neurological Disease. …

Recent advances in CAR-MSCs: the new engine of cellular immunotherapy evolution.

In recent years, the development of chimeric antigen receptor (CAR) technology has greatly promoted the progress of cellular immunotherapy. Among them, CAR-T cell therapy has shown remarkable clinical effects in the treatment of hematological malignancies. However, this therapy still faces a series of challenges, including immunogenicity, toxic side effects, and insufficient maintenance of long-term efficacy. The latest research progress has extended CAR technology to mesenchymal stem cells (MSCs), and the resulting CAR-MSCs combine the precise targeting ability of CAR molecules with the inher

Biomolecular condensates as dynamic regulators of musculoskeletal homeostasis, disease, and therapeutic challenges.

Biomolecular condensates are membraneless assemblies that concentrate proteins, nucleic acids, and other biomolecules into dynamic cellular compartments. Liquid-liquid phase separation (LLPS) is one important route by which such condensates form, particularly when multivalent interactions generate liquid-like, reversible assemblies. However, not every condensate or disease-associated assembly should be explained solely by LLPS. In the musculoskeletal system, condensates have been linked to transcription, signal transduction, RNA metabolism, stress responses, tissue development, homeostasis, an

Multiple myeloma, a quintessential malignant disease of aging: a geroscience perspective on pathogenesis and treatment.

Multiple myeloma (MM) is an incurable plasma cell malignancy, which is predominantly a disease of older adults (the median age at diagnosis is 70 years). The slow progression from asymptomatic stages and the late-onset of MM suggest fundamental differences compared to many other hematopoietic system-related malignancies. The concept discussed in this review is that age-related changes at the level of terminally differentiated plasma cells act as the main risk factors for the development of MM. Epigenetic and genetic changes that characterize both MM development and normal aging are highlighted

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… In senescent cells, global hypomethylation is accompanied by hypermethylation of the senescent-associated heterochromatin foci (SAHFs). The SAHFs are at the loci of proliferative genes such as E2F target genes, responsible for initiating the G1 phase of the cell cycle. …