Asian journal of urology · 2025
Systematic investigation of zinc finger MYND-type containing 11-mediated alternative splicing reveals notable events in prostate cancer.
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Lian Cheng, Wang Zixian, Gao Xu, Wei Gong-Hong
Аннотация
OBJECTIVE: Alternative splicing (AS) is increasingly recognized as a hallmark of cancer, contributing to tumor progression and therapeutic resistance. Zinc finger MYND-type containing 11 (ZMYND11), a critical reader of the histone modification H3.3K36me3, is frequently downregulated in various cancers. However, its specific role in regulating AS in prostate cancer (PCa) remains unclear. This study aimed to elucidate the mechanisms by which ZMYND11 modulates AS in PCa and evaluate its potential as a therapeutic target.
METHODS: The comprehensive AS analysis was conducted using two bioinformatics tools, SUPPA2 and rMATS, applied to data from ZMYND11 knockdown PCa cell lines and a large cohort of PCa patient samples. Candidate ZMYND11-mediated AS events were identified based on overlapping results from both tools. Experimental validation was performed in multiple PCa cell lines, and confirmed findings were classified as notable AS events.
RESULTS: SUPPA2, with a threshold of an absolute ΔPSI >0.1 and p-value <0.05, was identified as the optimal tool for detecting ZMYND11-mediated AS events. A total of 19 candidate AS events were identified, with approximately 50% involving exon skipping. Experimental validation highlighted three notable AS events affecting mitogen-activated protein kinase kinase kinase kinase 4 (MAP4K4), golgin B1 (GOLGB1), and Dmx like 1 (DMXL1). These events are implicated in key pathways influencing tumor growth and metastasis, underscoring the tumor-suppressive role of ZMYND11 in PCa.
CONCLUSION: This study systematically characterizes ZMYND11-mediated AS in PCa, revealing its pivotal role in modulating splicing events critical to tumor progression. The findings establish ZMYND11 as a potential biomarker and a promising source of novel therapeutic targets for PCa management.
METHODS: The comprehensive AS analysis was conducted using two bioinformatics tools, SUPPA2 and rMATS, applied to data from ZMYND11 knockdown PCa cell lines and a large cohort of PCa patient samples. Candidate ZMYND11-mediated AS events were identified based on overlapping results from both tools. Experimental validation was performed in multiple PCa cell lines, and confirmed findings were classified as notable AS events.
RESULTS: SUPPA2, with a threshold of an absolute ΔPSI >0.1 and p-value <0.05, was identified as the optimal tool for detecting ZMYND11-mediated AS events. A total of 19 candidate AS events were identified, with approximately 50% involving exon skipping. Experimental validation highlighted three notable AS events affecting mitogen-activated protein kinase kinase kinase kinase 4 (MAP4K4), golgin B1 (GOLGB1), and Dmx like 1 (DMXL1). These events are implicated in key pathways influencing tumor growth and metastasis, underscoring the tumor-suppressive role of ZMYND11 in PCa.
CONCLUSION: This study systematically characterizes ZMYND11-mediated AS in PCa, revealing its pivotal role in modulating splicing events critical to tumor progression. The findings establish ZMYND11 as a potential biomarker and a promising source of novel therapeutic targets for PCa management.