Silencing of the DNA Mismatch Repair Gene MLH1 Induced by Hypoxic Stress in a Pathway Dependent on the Histone Demethylase LSD1

Yuhong Lu, Narendra Wajapeyee, Mitchell S. Turker, Peter M. Glazer

Research output: Contribution to journalArticle

36 Scopus citations

Abstract

Silencing of MLH1 is frequently seen in sporadic colorectal cancers. We show here that hypoxia causes decreased histone H3 lysine 4 (H3K4) methylation at the MLH1 promoter via the action of the H3K4 demethylases LSD1 and PLU-1 and promotes durable long-term silencing in a pathwaythat requires LSD1. Knockdown of LSD1 or its corepressor, CoREST, also prevents the resilencing (and associated cytosine DNA methylation) of the endogenous MLH1 promoter in RKO colon cancer cells following transient reactivation by treatment with the DNA methyltransferase inhibitor5-aza-2'-deoxycytidine (5-aza-dC). The results demonstrate that hypoxia is a driving force for silencing of MLH1 and that the LSD1/CoREST complex is necessary for this process. The results reveal a mechanism by which hypoxia promotes cancer cell evolution to drive malignant progression through epigenetic modulation. Our findings suggest that LSD1/CoREST acts as a colon cancer oncogene by epigenetically silencing MLH1 and also identify the LSD1/CoREST complex as a potential target for therapy.

Original languageEnglish (US)
Pages (from-to)501-513
Number of pages13
JournalCell Reports
Volume8
Issue number2
DOIs
StatePublished - Jul 24 2014

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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