Castration resistant prostate cancer (CRPC) remains a major clinical challenge, as tumors at this stage are largely incurable. Cumulative evidence, including ours, suggests that the methyltransferase EZH2 represents a promising drug target for CRPC treatment. Although EZH2 is best known for its role as the catalytic subunit of Polycomb repressive complex 2 (PRC2), which methylates histone H3 on lys27 for gene silencing, additional functions of EZH2 have been indicated. It is in consistence with our prior work showing a specific transactivation function of EZH2 in CRPC, which requires its enzymatic activity and the ability as a co-activator for critical transcription factors such as the androgen receptor (AR). With the identification of targeted inhibitors against EZH2 methyltransferase activity, we were able to evaluate the biological effects of pharmacological inhibition of EZH2 in CRPC cells. Indeed, EZH2 inhibitor significantly retarded the growth of prostate cancer cells. Intriguingly, the inhibitor in CRPC cells didn't up-regulate the expression of EZH2-repressed genes, but instead significantly down-regulated the levels of EZH2-activated genes. Furthermore, AR methylation was modulated by EZH2 methyltransferase activity. Meanwhile, our proteomic analysis found ?-catenin, a well-known regulator of AR signaling, as one of EZH2-interacting proteins that are not associated with other components of PRC2 complex. All these compelling data reinforce our hypothesis that EZH2 exerts a polycomb-independent function linking to the AR signaling, which is critical for CRPC development. Therefore, I proposed to set up the preclinical models to test the efficacy of EZH2 inhibitor, either alone or combined with AR antagonists, in prostate cancer (Aim 1), and investigate the transcriptional network composed of EZH2, AR as well as ?-catenin in regulation of CRPC- related genes (Aim 2). I will further identify novel proteins that interact with EZH2 and determine its oncogenic functions (Aim 3). I am confident that our research will add an entirely new dimension to the field of cancer research, and provide a compelling foundation for the clinical practice of aggressive solid tumors.

Public Health Relevance

My work found that the selective inhibitor of EZH2 enzymatic activity significantly suppressed the androgen-independent growth of castration resistant prostate cancer (CRPC) cells, and induced a distinct genetic profile in CRPC, which involves EZH2 unconventional function in gene activation through methylation of critical transcription factors such as the androgen receptor (AR). Based on the compelling evidence, I proposed to assess the efficacy of EZH2 inhibitor, either alone or combined with AR antagonists, in the preclinical models of CRPC, and to investigate the polycomb-independent functions of EZH2, providing insightful information on the therapeutic strategies for aggressive tumors that are usually resistant to standard-of-care.

National Institute of Health (NIH)
Career Transition Award (K99)
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Subcommittee B - Comprehensiveness (NCI)
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Schmidt, Michael K
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Dana-Farber Cancer Institute
United States
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