MEN1 is a Melanoma Tumor Suppressor that Preserves Genomic Integrity by Stimulating Transcription of Genes that Promote Homologous Recombination-Directed DNA Repair

Abstract

Multiple endocrine neoplasia type 1 is a familial cancer syndrome resulting from loss-of-function mutations in the MEN1 gene. We previously identified the tumor suppressor MEN1 as a gene required for oncogene-induced senescence in melanocytes, raising the possibility that MEN1 is a melanoma tumor suppressor. Here we show that MEN1 expression is lost in a high percentage of human melanomas and melanoma cell lines. We find that melanocytes depleted of MEN1 are deficient in homologous recombination (HR)-directed DNA repair, which is accompanied by increased non-homologous end joining activity. Following DNA damage, MEN1 levels increase resulting from phosphorylation by the DNA damage kinase ATM/ATR. Most importantly, we show that MEN1 functions by directly stimulating transcription of several genes, including BRCA1, RAD51 and RAD51AP1, that encode proteins involved in HR. MEN1 and its coactivator, the histone methyltransferase MLL, are recruited to the BRCA1, RAD51 and RAD51AP1 promoters by estrogen receptor 1, resulting in increased histone H3-lysine 4 trimethylation and transcription. Collectively, our results indicate that MEN1 is a melanoma tumor suppressor that functions by stimulating transcription of genes involved in HR-directed DNA repair.