Regulation of USP37 Expression by REST-associated G9a-dependent Histone Methylation

The deubiquitylase (DUB) USP37 is a component of the ubiquitin system and controls cell proliferation by regulating the stability of the cyclin-dependent kinase inhibitor 1B, (CDKN1B/p27Kip1). The expression of USP37 is down-regulated in human medulloblastoma tumor specimens. In the current study we show that USP37 prevents medulloblastoma growth in mouse orthotopic models, suggesting that it has tumor suppressive properties in this neural cancer. Here, we also report on the mechanism underlying USP37 loss in medulloblastoma. Previously, we observed that the expression of USP37 is transcriptionally repressed by the RE1 Silencing Transcription Factor (REST), which requires chromatin remodeling factors for its activity. Genetic and pharmacological approaches were employed to identify a specific role for G9a, a histone methyltransferase (HMT), in promoting methylation of histone H3 lysine-9 (H3K9) mono- and di-methylation, and surprisingly tri-methylation, at the USP37 promoter to repress its gene expression. G9a inhibition also blocked the tumorigenic potential of medulloblastoma cells in vivo. Using isogenic low- and high-REST medulloblastoma cells, we further showed a REST-dependent elevation in G9a activity, which further increased mono- and tri-methylation of histone H3K9, accompanied by down regulation of USP37 expression. Together, these findings reveal a role for REST-associated G9a and histone H3K9 methylation in the repression of USP37 expression in medulloblastoma.