Chromatin Remodelers Are Frequently Disrupted By Epigenetic And Genetic Alterations At An Early Stage Of Carcinogenesis

Proceedings: AACR 106th Annual Meeting 2015; April 18-22, 2015; Philadelphia, PAChromatin remodeling factors (chromatin remodelers), such as SWI/SNF and ISWI complexes, regulate gene transcription by modulating chromatin accessibility. Genes encoding subunits of chromatin remodelers are frequently disrupted by loss of function mutations in various types of cancers. In contrast, inactivation of chromatin remodelers by epigenetic alterations, such as aberrant DNA methylation, is unknown. In this study, we aimed to clarify 1) whether or not chromatin remodelers are inactivated by aberrant DNA methylation, and 2) the timing of this occurrence.DNA methylation statuses of 16 genes encoding chromatin remodelers with promoter CpG islands were analyzed in non-cancerous tissues of male gastric cancer patients using an Infinium HumanMethylation450 BeadChip array. Among the 16 genes, two genes, ACTL6B and SMARCA1, were frequently methylated in non-cancerous gastric tissues. Among these genes, SMARCA1 was expressed at high levels in normal gastric tissues, but ACTL6B was not. In four of 50 primary gastric cancers, SMARCA1 was aberrantly methylated. It was re-expressed after treatment with a DNA demethylating agent, 5-aza-2′-deoxycytidine (5-aza-dC), in gastric cancer cell lines, AGS and GC2. Somatic mutations of 18 genes encoding chromatin remodelers were analyzed using a next-generation personal sequencer in the 50 primary gastric cancers. Nine genes, ARID1A, ARID1B, ARID2, SMARCA1, SMARCA2, SMARCA4, SMARCB1, PBRM1, and PHF10, were mutated in one or more of the 50 gastric cancers. The mutant allele frequency was close to the cancer cell content in cancer samples with a specific mutation of a chromatin remodeler. Depletion of a chromatin remodeler, SMARCA1 or SMARCA2, by shRNAs in cancer cell lines promoted their growth.These results showed that epigenetic and genetic alterations of chromatin remodelers are induced at an early stage of carcinogenesis (Takeshima et al., Cancer Letters, in press).Citation Format: Hideyuki Takeshima, Tohru Niwa, Takamasa Takahashi, Takayuki Ando, Hirokazu Taniguchi, Hitoshi Katai, Toshiro Sugiyama, Toshikazu Ushijima. Chromatin remodelers are frequently disrupted by epigenetic and genetic alterations at an early stage of carcinogenesis. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1048. doi:10.1158/1538-7445.AM2015-1048