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How YTHDC1/EZH2-mediated Crosstalk between RNA and Histone Methylation Regulates Prostate Cancer Progression

By Stuart P. Atkinson, Ph.D.

March 25, 2026

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EZH2, YTHDC1, and Prostate Cancer Development: A Complex Story

The development of advanced, aggressive prostate cancer occurs alongside significant epigenetic alterations (Ge et al.) thanks, in part, to the persistent upregulation/activation of the H3K27 histone methyltransferase EZH2 (Enhancer Of Zeste 2 Polycomb Repressive Complex 2 Subunit) (Davies et al.). EZH2 constitutes a common component of two closely related PRC2 (Polycomb Repressive Complex 2) forms that differ with regard to their accessory subunits (Macrae et al.), which may alter PRC2 recruitment to chromatin and, hence, their overall function (van Mierlo et al.). These accessory subunits may support the observed reactivation of EZH2-silenced genes essential for tumor development during prostate cancer progression. Adding further complexity to the situation, newly produced (or “nascent”) RNA can function as a “bridge” linking the distinct PRC2 forms to chromatin and thereby participate in PRC2 recruitment and the regulation of gene transcription (Long et al.). A related study also demonstrated that nascent RNA can both promote and inhibit gene expression by regulating the PRC2-mediated deposition of H3K27me3 (Li et al.).

A recent article published in PNAS from researchers led by Xing-Huan Wang, Xian-Tao Zeng (Wuhan University), and Hailiang Hu (Southern University of Science and Technology) recently linked the elevated expression of the long isoform (PHF19L) of the PRC2.1 accessory subunit PHF19 (PHD Finger Protein 19) to tumor progression and therapeutic resistance in advanced prostate cancer (Yuan, Ming, He, Liu, and He et al.). Importantly, previous studies had reported the involvement of PHF19 in PRC2 recruitment and the complex role of PHF19 in H3K27me3 deposition and gene-specific transcriptional regulation (Jain et al., Vizán et al., Ren et al., and Ballaré et al.). Furthermore, this new study revealed that PHF19L recruitment to m6^A (N⁶-methyladenosine)-modified nascent RNA via the YTHDC1 (YTH Domain Containing 1) nuclear m6^A “reader” (Jaafar & Aguiar), which plays a central role in the regulation of histone modifications (Liu et al. & Chen et al.), helped to form a biomolecular condensate that pulls PRC2/EZH2 away from chromatin, resulting in reduced H3K27me3 deposition and the reactivation of EZH2-silenced target genes during prostate cancer progression. Of note, previous research had demonstrated that YTHDC1 plays a significant role in regulating the fate of m6^A-modified nuclear mRNAs (Widagdo et al.), and that the formation of nuclear condensates of YTHDC1-m6A-modified RNA helps to maintain mRNA stability or stimulate gene activation (Lee et al. and Cheng et al.).

Overall, this exciting new study describes the intrinsic (and complex) crosstalk taking place between RNA methylation (via YTHDC1) and histone modifications (via EZH2), which may provide therapeutic targets for advanced prostate cancer.

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How YTHDC1/EZH2-mediated Crosstalk Supports the Re-expression of Epigenetically Silenced Genes

The analysis of PRC2 accessory subunit expression during prostate cancer progression served as the starting point of this new study; as such, the authors discovered a gradual upregulation of PHF19L expression, which played an EZH2-dependent tumor-promoting role by alleviating the suppression of EZH2-targeted genes. In fact, they found that PHF19L pulled EZH2 off chromatin by forming a liquid-like biomolecular condensate with m6^A-modified nascent RNA-bound YTHDC1, leading to reduced levels of H3K27me3 and a subsequent switch from gene silencing to gene expression. Overall, this finding supported the hypothesis that nascent RNA can promote gene expression by pulling EZH2 off chromatin via the YTHDC1-PHF19L complex. PHF19L colocalized with YTHDC1 to form a co-phase-separated condensate in a nascent RNA- and m6^A-dependent manner and displayed slow dynamics, which may limit the exchange of factors such as EZH2 with the surrounding liquid and hence result in a lower level of H3K27me3 deposition and the activation of previously silenced promoters. Interestingly, the study also revealed that specific cancer-associated transcription factors (such as MYC, AP-1, and HSF1) may cooperate with EZH2 to modulate the transcription of genes regulated by this regulatory mechanism (which included TGM2, SPHK1, and RUNX1). However, the authors highlight one important question that remains unanswered: how do biomolecular condensates specifically select target genes?

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YTHDC1-EZH2-mediated Crosstalk: Conclusions and Unresolved Concepts?

Overall, this exciting new study cuts through the complexity and reports that crosstalk between RNA methylation (via the m6A reader YTHDC1) and histone methylation (via EZH2), along with the formation of biomolecular condensates, can explain how EZH2-silenced genes essential for tumor progression become reactivated in cases of advanced prostate cancer. Could this newly described epigenetic mechanism provide novel targets for the development of efficient therapies for advanced, aggressive prostate cancer cases? Keep an eye on the Epigenetics Blog at Active Motif to find out!

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YTHDs in Epigenetics and Disease

The YTHD pathway, which encompasses the cellular signaling and regulatory processes mediated by YTH-domain proteins, is a central component of the m6A RNA modification system, in which YTH-domain proteins function as readers that recognize m6^A-modified RNA to regulate stability, splicing, translation, and decay. m6A constitutes the most abundant internal modification in eukaryotic mRNA, interpreted primarily by proteins such as YTHDF1–3 and YTHDC1–2. Of note, the dysregulation of these proteins has been linked to cancer, metabolic disorders, infertility, and neurological diseases. For more information and related products, check out our new “YTHDs in Epigenetics and Disease” page.

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About the author

Stuart P. Atkinson, Ph.D.

Stuart was born and grew up in the idyllic town of Lanark (Scotland). He later studied biochemistry at the University of Strathclyde in Glasgow (Scotland) before gaining his Ph.D. in medical oncology; his thesis described the epigenetic regulation of the telomerase gene promoters in cancer cells. Following Post-doctoral stays in Newcastle (England) and Valencia (Spain) where his varied research aims included the exploration of epigenetics in embryonic and induced pluripotent stem cells, Stuart moved into project management and scientific writing/editing where his current interests include polymer chemistry, cancer research, regenerative medicine, and epigenetics. While not glued to his laptop, Stuart enjoys exploring the Spanish mountains and coastlines (and everywhere in between) and the food and drink that it provides!

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