Lineage-specific canonical and non-canonical activity of EZH2 in advanced prostate cancer subtypes

• Published in: Nature communications Vol. 15; no. 1; pp. 6779 - 15
• Main Authors: Venkadakrishnan, Varadha Balaji, Presser, Adam G., Singh, Richa, Booker, Matthew A., Traphagen, Nicole A., Weng, Kenny, Voss, Nathaniel C. E., Mahadevan, Navin R., Mizuno, Kei, Puca, Loredana, Idahor, Osasenaga, Ku, Sheng-Yu, Bakht, Martin K., Borah, Ashir A., Herbert, Zachary T., Tolstorukov, Michael Y., Barbie, David A., Rickman, David S., Brown, Myles, Beltran, Himisha
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 08.08.2024; Nature Publishing Group; Nature Portfolio
• Subjects: 13/106; 13/31; 13/51; 38/15; 38/91; 631/67/1059/602; 631/67/1459/1963; 631/67/589/466; 631/67/68/2486; 82/29; Adenocarcinoma; Adenocarcinoma - genetics; Adenocarcinoma - metabolism; Adenocarcinoma - pathology; Animals; ASCL1 protein; Castration; Cell cycle; Cell Differentiation; Cell Line, Tumor; Cell Lineage; Cycle ratio; Disease resistance; Drug Resistance, Neoplasm - genetics; Endocrine therapy; Enhancer of Zeste Homolog 2 Protein - genetics; Enhancer of Zeste Homolog 2 Protein - metabolism; Gene Expression Regulation, Neoplastic; Genes; Histone methyltransferase; Humanities and Social Sciences; Humans; Male; Mice; multidisciplinary; Prostate cancer; Prostatic Neoplasms - genetics; Prostatic Neoplasms - metabolism; Prostatic Neoplasms - pathology; Prostatic Neoplasms, Castration-Resistant - drug therapy; Prostatic Neoplasms, Castration-Resistant - genetics; Prostatic Neoplasms, Castration-Resistant - metabolism; Prostatic Neoplasms, Castration-Resistant - pathology; Science; Science (multidisciplinary); Therapeutic targets
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-024-51156-5

Enhancer of zeste homolog 2 (EZH2) is a histone methyltransferase and emerging therapeutic target that is overexpressed in most castration-resistant prostate cancers and implicated as a driver of disease progression and resistance to hormonal therapies. Here we define the lineage-specific action and differential activity of EZH2 in both prostate adenocarcinoma and neuroendocrine prostate cancer (NEPC) subtypes of advanced prostate cancer to better understand the role of EZH2 in modulating differentiation, lineage plasticity, and to identify mediators of response and resistance to EZH2 inhibitor therapy. Mechanistically, EZH2 modulates bivalent genes that results in upregulation of NEPC-associated transcriptional drivers (e.g., ASCL1 ) and neuronal gene programs in NEPC, and leads to forward differentiation after targeting EZH2 in NEPC. Subtype-specific downstream effects of EZH2 inhibition on cell cycle genes support the potential rationale for co-targeting cyclin/CDK to overcome resistance to EZH2 inhibition. Enhancer of zeste homolog 2 (EZH2) has been implicated as a driver of disease progression and resistance to hormonal therapies. Here, the authors focus on EZH2 in two subtypes of advanced prostate cancer and report how it modulates the bivalent genes thereby leading to forward differentiation after being targeted in neuroendocrine prostate cancer.