Abstract
Abstract Hypoxia is a key microenviromental stress in solid tumors that is associated with poor prognosis. It has been indicated that hypoxia induces genetic instability through multiple mechanisms. Previously, we have shown that BRCA1 and RAD51, in the homology dependent repair (HDR) pathway, and MLH1 and MSH2, key components of MMR, are down-regulated at the transcriptional level in response to hypoxia. Here we show that hypoxia also drives epigenetic modification of the BRCA1 and MLH1 promoters, with decreased H3K4 methylation as a key repressive modification produced by the lysine specific histone demethylase, LSD1. In cells containing the BRCA1 promoter driving a selectable HPRT gene, long-term silencing of the promoter was observed following exposure to hypoxic stress. The silenced clones showed decreased H3K4 methylation and decreased H3K9 acetylation in the BRCA1 promoters, consistent with the acute effects of hypoxic stress. Similarly, we also found that hypoxia causes durable long-term silencing of the MLH1 promoter in a pathway that requires LSD1. Knockdown of LSD1 or its co-repressor, CoREST, also prevents the re-silencing (and associated cytosine DNA methylation) of the endogenous MLH1 promoter in RKO colon cancer cells following transient reactivation by treatment with the DNA methyltransferase inhibitor 5-aza-2′-deoxycytidine (5-aza-dC). These results suggest that hypoxia is a driving force for long-term silencing of DNA repair genes, including BRCA1 and MLH1, thereby promoting genome instability and tumor progression. Citation Format: Yuhong Lu, Adrian Chu, Narendra Wajapeyee, Mitchell S. Turker, Peter M. Glazer. Epigenetic silencing of the DNA repair genes, BRCA1 and MLH1, induced by hypoxic stress in a pathway dependent on the histone demethylase, LSD1. [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 2887. doi:10.1158/1538-7445.AM2015-2887
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