title: Silencing of the DNA mismatch repair gene MLH1 induced by hypoxic stress in a pathway dependent on the histone demethylase LSD1.
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 pathway that 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 inhibitor 5-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.
authors.affiliation: Department of Therapeutic Radiology, Yale School of Medicine, New Haven, CT 06520, USA.
authors.forename: Yuhong
authors.initials: Y
authors.lastname: Lu
authors.affiliation: Department of Pathology, Yale School of Medicine, New Haven, CT 06520, USA.
authors.forename: Narendra
authors.initials: N
authors.lastname: Wajapeyee
authors.affiliation: Department of Molecular and Medical Genetics, Oregon Health & Science University, Portland, OR 97239, USA; Center for Research on Occupational and Environmental Toxicology, Oregon Health & Science University, Portland, OR 97239, USA.
authors.forename: Mitchell S
authors.initials: MS
authors.lastname: Turker
authors.affiliation: Department of Therapeutic Radiology, Yale School of Medicine, New Haven, CT 06520, USA; Department of Genetics, Yale School of Medicine, New Haven, CT 06520, USA. Electronic address: peter.glazer@yale.edu.
authors.forename: Peter M
authors.initials: PM
authors.lastname: Glazer
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D001374:Azacitidine / Q000031:analogs & derivatives / Q000494:pharmacology; D015687:Cell Hypoxia; D056970:Co-Repressor Proteins / Q000235:genetics / Q000378:metabolism; D003110:Colonic Neoplasms / Q000235:genetics* / Q000378:metabolism; D015254:DNA Modification Methylases / Q000037:antagonists & inhibitors; D000077209:Decitabine; D020868:Gene Silencing; D006367:HeLa Cells; D056466:Histone Demethylases / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D061986:MCF-7 Cells; D000070957:MutL Protein Homolog 1; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D056970:Co-Repressor Proteins; C501486:MLH1 protein, human; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; C121019:RCOR1 protein, human; D000077209:Decitabine; D056466:Histone Demethylases; C495195:KDM1A protein, human; D015254:DNA Modification Methylases; D000070957:MutL Protein Homolog 1; D001374:Azacitidine