The H2A Ubiquitin Ligase TRIM37 Is a Breast Cancer Oncoprotein

Approximately 40% of breast cancers harbor amplification of the chromosomal region 17q23, which includes the tripartite motif containing 37 (TRIM37) gene. TRIM37 encodes a protein with an E3 ubiquitin ligase RING finger domain and has been implicated in epigenetic silencing; however, its substrates remain unidentified. Bhatnagar and colleagues found that TRIM37 directly mediated histone H2A monoubiquitination, which serves as a repressive histone mark. In breast cancer cell lines harboring 17q23 amplification, TRIM37 was overexpressed and associated with decreased expression of the major H2A ubiquitin ligase ring finger protein 2 (RNF2), which silences gene expression via interaction with Polycomb repressive complex (PRC) 1. Unbiased genome-wide analysis of TRIM37 binding sites revealed enrichment for ubiquitinated H2A at TRIM37 target genes, and knockdown of TRIM37, but not RNF2, resulted in a significant reduction in ubiquitinated H2A levels specifically in cells with 17q23 amplification. In addition, knockdown of TRIM37 resulted in increased expression of TRIM37 target genes, which included many putative tumor suppressors. Mechanistically, TRIM37 associated with PRC2 at the promoters of target genes and altered the specificity of PRC2, resulting in histone H3 lysine 27 trimethylation and transcriptional silencing of these genes. Analysis of human breast cancer samples revealed that increased TRIM37 expression was correlated with reduced expression of a subset of TRIM37 target genes and decreased survival in patients with estrogen receptor (ER)–positive breast cancer. Furthermore, depletion of TRIM37 in 17q23-amplified breast cancer cells reduced xenograft tumor growth, whereas ectopic TRIM37 overexpression decreased TRIM37 target gene expression and was sufficient to promote tumor formation by nontransformed cells in vivo. In sum, these data identify TRIM37 as a histone H2A ubiquitin ligase and breast cancer oncogene that stimulates transformation via transcriptional repression of tumor suppressor genes.

Bhatnagar S, Gazin C, Chamberlain L, Ou J, Zhu X, Tushir JS, et al. TRIM37 is a new histone H2A ubiquitin ligase and breast cancer oncoprotein. Nature 2014;516:116–20.