Abstract B44: Accelerated mouse colorectal cancer progression in the presence of EHMT2 overexpression

In the last 5 years, the prevalence of colorectal cancer (CRC) has increased worldwide and has surpassed that of liver cancer. Even after treatment for primary CRC, patients still have a high risk (30%–50%) of cancer recurrence, generally from metastasis. Thus, if we can uncover the progressive mechanisms of CRC and identify a novel drug target, current treatment regimens and the survival of patients with advanced stage CRC can be improved. Euchromatin histone lysine N-methyl transferase 2 (EHMT2) inhibition is considered an effective therapeutic strategy for cancer treatment because its inhibitors, BIX-01294 and UNC0639, can induce autophagy-dependent cell death. However, the function of EHMT2 in CRC progression remains largely unclear. In this study, we established a colonic stem-cell-specific EHMT2 activation combined with sporadic (AOM/DSS-induced) or hereditary (Apc mutant) CRC mouse models. In the EHMT2-overexpressed group, many colonic tumors larger than 3 mm in size were found in the 24 weeks after tumor induction. Histological analysis of these tumors showed that the adenocarcinomatous glands became highly irregular, and these glands were difficult to discern, one of the characteristic of malignant CRC. In the 52 weeks after tumor induction, we reproducibly observed CRC liver metastases. Further analysis by RNA sequencing combined with gene set enrichment analysis determined that the anti-apoptosis-related and Wnt-signaling gene sets can be enriched in the EHMT2-overexpressed group. Using the chromatin immunoprecipitation assay, we demonstrated that EHMT2 directly targeted the caspase8 proximal promoter region and increased the level of H3 lysine9 di-methylation in this region. Several functional assays supported that this gene regulation may have conferred opportunities for CRC cells to avoid the cytotoxicity of anticancer drugs. Overall, aberrant EHMT2 expression is conducive to CRC progression. Citation Format: Kang-Yu Tai, I-Shing Yu, Shih-Ting Cha, Shu-Wha Lin, Min-Liang Kuo, You-Tzung Chen. Accelerated mouse colorectal cancer progression in the presence of EHMT2 overexpression. [abstract]. In: Proceedings of the AACR Special Conference on Chromatin and Epigenetics in Cancer; Sep 24-27, 2015; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2016;76(2 Suppl):Abstract nr B44.