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 nonhomologous end-joining activity. Following DNA damage, MEN1 levels increase as a result of phosphorylation by the DNA damage kinase ATM/ATR. Most importantly, we show that MEN1 functions by directly stimulating the transcription of several genes, including BRCA1, RAD51, and RAD51AP1, that encode proteins involved in HR. MEN1 and its coactivator, the mixed-lineage leukemia histone methyltransferase, 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 the transcription of genes involved in HR-directed DNA repair.

ACKNOWLEDGMENTS

We thank Robert Weinberg, Settara C. Chandrasekharappa, Michael Kastan, and Mark Meuth for reagents; Peter C. Scacheri for the sharing the database of MEN1 targets; Xiaochun Zhu for assistance with immunofluorescence assays; Jianhong Ou and Lihua Julie Zhu for assistance with statistical analysis; and Sara Deibler for editorial assistance.

N.W. is a Translational Scholar of the Sidney Kimmel Foundation for Cancer Research. This work was supported by U.S. National Institutes of Health grant R01GM033977 to M.R.G. M.R.G. is an investigator of the Howard Hughes Medical Institute.