Pharmacological inhibition of the epigenetic writer EZH2 in castration resistant prostate cancer

Cancer Diagnostics Conference & Expo

June 13-15, 2016 Rome, Italy

Kexin Xu

University of Texas Health Science Center at San Antonio, USA

Posters & Accepted Abstracts: J Cancer Sci Ther

Abstract :

Pharmacological inhibition of the methyltransferase EZH2 has been proposed as a promising anticancer strategy. Selective small-molecule inhibitors that disrupt EZH2 enzymatic activity preferentially suppress the growth of lymphoma cells with activating mutations in EZH2 gene. Although substantial evidence indicates a vital role of EZH2 in driving the aggressive features of cancer cells, it is unknown whether these EZH2-targeting compounds have inhibitory effects in solid tumors that generally do not carry somatic mutations of the methyltransferase. We tested two distinct EZH2 inhibitors in a panel of human prostate cell lines, and found that both were effective in blocking the proliferation of cancer cells with competent androgen receptor (AR) signaling, especially the castration resistant prostate cancer (CRPC) cells. Quantitative ChIP-Seq revealed a significant reduction in global H3K27 trimethylation (H3K27me3) levels in both sensitive and irresponsive prostate cancer cells upon the inhibitor treatment. In sensitive CRPC cells, however, both drugs induced a specific gene signature that is highly associated with AR signaling. Compound treatment disrupted the interaction between EZH2 and AR, and impaired AR recruitment to its target gene loci. EZH2 inhibitor showed significant efficacies in CRPC xenograft mouse models as monotherapy, and was even more effective in hindering the androgen-independent growth of CRPC cells when combined with second-generation antiandrogens. Our data demonstrate that pharmacological inhibition of EZH2 activity, either alone or in combination with AR antagonists, represents a promising strategy for the treatment of advanced prostate cancer.

Biography :

Email: XuK3@uthscsa.edu