ArticleOncogene2026
EZH2 PROTACs outperform catalytic inhibitors in prostate cancer by targeting a methylation-independent function of PRC2.
Article in Oncogene, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 4 papers.
What it found
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Who cites it
4 citing papers in PubMed.
- PROTACs in cancer therapy: targeted degradation of GPX4, PARP and epigenetic regulators.Journal of enzyme inhibition and medicinal chemistry · 2026Review
- Inflammatory and Epigenetic Biomarkers in Prostate Disease: Current Evidence, Clinical Limitations, and Future Multimarker Strategies.Diagnostics (Basel, Switzerland) · 2026Review
- PM2.5 toxin benzo[a]pyrene induces life-limiting inflammation and oxidative stress in the airway by up-regulation of TRPC6 and inactivation of β2AR/CFTR signaling.bioRxiv : the preprint server for biology · 2026Article
- The molecular underpinnings of the immune landscape in prostate cancer: decoding a "cold" tumor.Frontiers in oncology · 2026Review
Corrections and comments
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Authors and funding
21 authors.
Funding
Abstract
Enhancer of Zeste Homolog 2 (EZH2) is the enzymatic subunit of the Polycomb Repressive Complex 2 (PRC2). It catalyzes H3K27 methylation for epigenetic silencing of tumor suppressors and critically drives prostate cancer (PCa) progression. However, inhibitors of EZH2 catalytic function (EZH2i), such as EPZ-6438, showed limited efficacy in PCa. Here, we designed and developed a series of VHL-based proteolysis-targeting chimera (PROTAC) degraders of EZH2 using EPZ-6438 as a ligand and identified PROTAC-6272 as a lead compound. PROTAC-6272 effectively degraded EZH2 and other PRC2 subunits across diverse PCa cell lines. However, PROTAC-6272 and other similar EZH2i-based PROTACs were consistently unable to decrease androgen receptor (AR), a gene that is directly activated by solo EZH2. Mechanistically, EZH2 PROTACs failed to degrade EZH2 coactivators, such as p300, due to their inability to engage EZH2 outside of the PRC2 complex. Nevertheless, PROTAC-6272 exhibited anti-proliferative activities superior to EPZ-6438 in some PCa models, wherein it induced p21 expression and cellular senescence by disrupting a methylation-independent PRC2 function. In summary, while EZH2i-based PROTACs failed to target the PRC2-independent functions of EZH2, they confer added benefits over EPZ-6438 by abolishing a polycomb-dependent but methylation-independent function of EZH2, offering therapeutic advantages in some PCa.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.