Abstract 4500: An AR-regulated kinase CCRK activates a tumor-initiating circuitry through dual regulation of EZH2
Authors: Cheng Alfred S. L. , Feng Hai , Yu Zhuo , Lee Ying-Ying , Li May S. , Cheung Yue-Sun , Lai Paul B.S. , Sung Joseph J.Y. 
Published: May 2015

Hepatocellular carcinoma (HCC) is one of the commonest and deadliest cancers worldwide with a striking gender prevalence observed in men. Androgen receptor (AR) is a ligand-activated nuclear receptor that regulates the development of male sexual phenotype. Aberrant AR signaling, however, has detrimental consequences in the development of male-predominant cancers. Using genome-wide location analysis, we have recently uncovered cell cycle-related kinase (CCRK) as an AR direct transcriptional target that drives aberrant hepatocellular proliferation and tumorigenicity through β-catenin/T cell factor signaling (Feng et al. 2011). We also found that the Polycomb protein EZH2 promotes β-catenin-dependent hepatocarcinogenesis through concordant repression of Wnt antagonists via histone H3 lysine 27 trimethylation (Cheng et al. 2011). Recent studies have revealed the Polycomb-independent role of EZH2 in gene activation via AKT-mediated phosphorylation, however, the regulation and signaling network of EZH2 in HCC are poorly-understood. Here we show that the AR-regulated kinase CCRK activates a tumor-initiating circuitry by dual regulation of EZH2. Activation of CCRK phosphorylates glycogen synthase kinase 3β (GSK-3β) and AKT leading to transcriptional up-regulation and phosphorylation of EZH2 at Ser21 (pEZH2Ser9), respectively. pEZH2Ser9 in turn physically interacts with AR and cooperatively activate CCRK transcription via direct binding to the CCRK promoter, thus forming a feedback circuitry. In a chemical-induced murine HCC model, activation of the AR/CCRK/EZH2 regulatory loop precedes HCC formation, which is significantly reduced (&gt;80%) by lentiviral-mediated knockdown of CCRK. In human HCC tissues, these proteins are highly up-regulated, starting from the adjacent precancerous liver tissues. Most importantly, hyper-activation of this loop is significantly associated with shorter overall (p&lt;0.0001) and disease-free survival rates (p&lt;0.01) of the HCC patients. This study not only advances our fundamental understanding of the gender disparity in HCC, but also provides a new paradigm for nuclear receptor regulation of cancer epigenome. Elucidating the detailed signaling network of AR/CCRK/EZH2 will lead to the discovery and development of targeted therapies tailored to inhibit cancer-specific pathways. This study was supported by a CUHK Focused Investments Scheme - Scheme B (fis1112/0674/12yc), a National Natural Science Foundation of China (373492), a Health and Medical Research Fund (12110532) and a General Research Fund (462710).

References:

1. Feng H, et al. Cell cycle-related kinase is a direct androgen receptor-regulated gene that drives β-catenin/T cell factor-dependent hepatocarcinogenesis. J Clin Invest. 2011;121:3159-75.

2. Cheng AS, et al. EZH2-mediated concordant repression of Wnt antagonists promotes β-catenin-dependent hepatocarcinogenesis. Cancer Res. 2011;71:4028-39.

Citation Format: Alfred S. L. Cheng, Hai Feng, Zhuo Yu, Ying-Ying Lee, May S. Li, Yue-Sun Cheung, Paul B.S. Lai, Joseph J.Y. Sung. An AR-regulated kinase CCRK activates a tumor-initiating circuitry through dual regulation of EZH2. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4500. doi:10.1158/1538-7445.AM2014-4500