Abstract 5388: Molecular profiling of protein methyltransferases in prostate cancer and their clinical significance

Abstract

Abstract Prostate cancer is one of the most commonly diagnosed cancers among men worldwide. Most deaths of prostate cancer patients occur after the disease has progressed to castration-resistant prostate cancer, accompanied by metastatic dissemination and resistance to androgen-deprivation therapy. Therefore, an urgent need exists to identify druggable targets that will improve the treatment of this deadly and devastating disease. Epigenetic alteration has been identified as one the major causes of prostate cancer. Protein methyltransferases (PMTs), a large class of epigenetic enzymes that add one or more methyl groups to lysine (K) and arginine (R) residues on histones and non-histone proteins, play critical roles in chromatin function, transcriptional regulation, genomic stability, DNA repair and RNA metabolism. Although dysregulation of several PMTs has been reported in prostate cancers, there has been no systematic analysis of genomic anomalies and expression of PMTs in prostate cancer. In addition, the clinical relevance of alterations of each PMT in prostate cancer has yet to be fully explored. Here, we performed an integrated genomic and transcriptomic analysis of 68 PMT genes in prostate cancer (TCGA dataset) and identified associations among recurrent copy number alterations, gene expressions, clinicopathological features, and survival of patients. In addition to well-known EZH2 and WHSC1, we identified several additional PTMs, including SETDB1, SETD5 and PRDM12, which were significantly overexpressed in high-grade and high-stage prostate cancer. We also found that SETDB1 overexpression was significantly associated with biochemical recurrence of prostate cancer patients. To assess the contribution of endogenous SETDB1 overexpression to prostate cancer growth and progression, we examined the effects of knocking down SETDB1 in two prostate cancer cell lines CWR22Rv1 and DU-145. SETDB1 knockdown dramatically reduced CWR22Rv1 and DU-145 cell growth compared with the non-silencing control. We also identified all SETDB1 binding sites across the human genome in DU-145 prostate cancer cells by using an unbiased ChIP-seq approach. In summary, our integrated genomic and transcriptomic analysis identified a broad spectrum of genetic alterations in PMT genes involved in prostate cancer progression. Our findings suggest a promising avenue for future research—to focus on a subset of PMTs to better understand the molecular mechanisms and to identify therapeutic targets in prostate cancer. Citation Format: Yuanyuan Jiang, Lanxin Liu, David Weinfeld, Wenqi Shan, Huimei Yu, Xuhui Guo, Zhe Yang, Zeng-Quan Yang. Molecular profiling of protein methyltransferases in prostate cancer and their clinical significance [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5388. doi:10.1158/1538-7445.AM2017-5388