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
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
Harvard Medical School, Boston, MA, USA.
Nat Commun. 2024 Aug 8;15(1):6779. 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.
zeste同源物2增强子（EZH2）是一种组蛋白甲基转移酶，也是新兴的治疗靶点，在大多数去势抵抗性前列腺癌中过度表达，被认为是疾病进展和激素治疗耐药的驱动因素。在此，我们定义了EZH2在晚期前列腺癌的前列腺腺癌和神经内分泌前列腺癌（NEPC）亚型中的谱系特异性作用和差异活性，以更好地理解EZH2在调节分化、谱系可塑性中的作用，并识别对EZH2抑制剂治疗反应和耐药的介质。从机制上讲，EZH2调节二价基因，导致NEPC中NEPC相关转录驱动因子（如ASCL1）和神经元基因程序的上调，并在NEPC中靶向EZH2后导致正向分化。EZH2抑制对细胞周期基因的亚型特异性下游效应支持了联合靶向细胞周期蛋白/细胞周期蛋白依赖性激酶以克服对EZH2抑制耐药的潜在理论依据。
