TRIM37 is a new histone H2A ubiquitin ligase and breast cancer oncoprotein.

Abstract

The TRIM37 (or MUL) gene is located in the 17q23 chromosomal region, which is amplified in up to ~40% of breast cancers1. TRIM37 contains a RING finger domain, a hallmark of E3 ubiquitin ligases2, but its protein substrate(s) is unknown. Here we report that TRIM37 mono-ubiquitinates histone H2A, a chromatin modification associated with transcriptional repression3. We find that in human breast cancer cell lines containing amplified 17q23, TRIM37 is upregulated and, reciprocally, the major H2A ubiquitin ligase RNF23,4 (also called RING1B) is downregulated. Genome-wide chromatin immunoprecipitation (ChIP)-chip experiments in 17q23-amplified breast cancer cells identified many genes, including multiple tumour suppressors, whose promoters were bound by TRIM37 and enriched for ubiquitinated H2A (H2A-ub). However, unlike RNF2, which is a subunit of Polycomb repressive complex 1 (PRC1)3–5, we find that TRIM37 associates with Polycomb repressive complex 2 (PRC2). TRIM37, PRC2 and PRC1 are co-bound to specific target genes resulting in their transcriptional silencing. RNA interference (RNAi)-mediated knockdown of TRIM37 results in loss of H2A-ub, dissociation of PRC1 and PRC2 from target promoters, and transcriptional reactivation of silenced genes. Knockdown of TRIM37 in human breast cancer cells containing amplified 17q23 substantially decreases tumour growth in mouse xenografts. Conversely, ectopic expression of TRIM37 renders non-transformed cells tumorigenic. Collectively, our results reveal TRIM37 as an oncogenic H2A ubiquitin ligase that is overexpressed in a subset of breast cancers and promotes transformation by facilitating silencing of tumour suppressors and other genes.