title: TRIM37 is a new histone H2A ubiquitin ligase and breast cancer oncoprotein.
abstract: The TRIM37 (also known as MUL) gene is located in the 17q23 chromosomal region, which is amplified in up to ∼ 40% of breast cancers. TRIM37 contains a RING finger domain, a hallmark of E3 ubiquitin ligases, but its protein substrate(s) is unknown. Here we report that TRIM37 mono-ubiquitinates histone H2A, a chromatin modification associated with transcriptional repression. We find that in human breast cancer cell lines containing amplified 17q23, TRIM37 is upregulated and, reciprocally, the major H2A ubiquitin ligase RNF2 (also known as 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. However, unlike RNF2, which is a subunit of polycomb repressive complex 1 (PRC1), 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-mediated knockdown of TRIM37 results in loss of ubiquitinated H2A, 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.
authors.affiliation: 1] Howard Hughes Medical Institute, University of Massachusetts Medical School, Worcester, Massachusetts 01605, USA [2] Programs in Gene Function and Expression and Molecular Medicine, University of Massachusetts Medical School, Worcester, Massachusetts 01605, USA.
authors.forename: Sanchita
authors.initials: S
authors.lastname: Bhatnagar
authors.affiliation: CEA/DSV/iRCM/LEFG, Genopole G2, and Université Paris Diderot, 91057 Evry, France.
authors.forename: Claude
authors.initials: C
authors.lastname: Gazin
authors.affiliation: 1] Howard Hughes Medical Institute, University of Massachusetts Medical School, Worcester, Massachusetts 01605, USA [2] Programs in Gene Function and Expression and Molecular Medicine, University of Massachusetts Medical School, Worcester, Massachusetts 01605, USA.
authors.forename: Lynn
authors.initials: L
authors.lastname: Chamberlain
authors.affiliation: Programs in Gene Function and Expression and Molecular Medicine, University of Massachusetts Medical School, Worcester, Massachusetts 01605, USA.
authors.forename: Jianhong
authors.initials: J
authors.lastname: Ou
authors.affiliation: 1] Howard Hughes Medical Institute, University of Massachusetts Medical School, Worcester, Massachusetts 01605, USA [2] Programs in Gene Function and Expression and Molecular Medicine, University of Massachusetts Medical School, Worcester, Massachusetts 01605, USA.
authors.forename: Xiaochun
authors.initials: X
authors.lastname: Zhu
authors.affiliation: Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, Connecticut 06877, USA.
authors.forename: Jogender S
authors.initials: JS
authors.lastname: Tushir
authors.affiliation: 1] Howard Hughes Medical Institute, University of Massachusetts Medical School, Worcester, Massachusetts 01605, USA [2] Programs in Gene Function and Expression and Molecular Medicine, University of Massachusetts Medical School, Worcester, Massachusetts 01605, USA.
authors.forename: Ching-Man
authors.initials: CM
authors.lastname: Virbasius
authors.affiliation: 1] Howard Hughes Medical Institute, University of Massachusetts Medical School, Worcester, Massachusetts 01605, USA [2] Programs in Gene Function and Expression and Molecular Medicine, University of Massachusetts Medical School, Worcester, Massachusetts 01605, USA.
authors.forename: Ling
authors.initials: L
authors.lastname: Lin
authors.affiliation: 1] Programs in Gene Function and Expression and Molecular Medicine, University of Massachusetts Medical School, Worcester, Massachusetts 01605, USA [2] Program in Bioinformatics and Integrative Biology, University of Massachusetts Medical School, Worcester, Massachusetts 01605, USA.
authors.forename: Lihua J
authors.initials: LJ
authors.lastname: Zhu
authors.affiliation: Department of Pathology, Yale University School of Medicine, New Haven, Connecticut 06520, USA.
authors.forename: Narendra
authors.initials: N
authors.lastname: Wajapeyee
authors.affiliation: 1] Howard Hughes Medical Institute, University of Massachusetts Medical School, Worcester, Massachusetts 01605, USA [2] Programs in Gene Function and Expression and Molecular Medicine, University of Massachusetts Medical School, Worcester, Massachusetts 01605, USA.
authors.forename: Michael R
authors.initials: MR
authors.lastname: Green
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000201:enzymology* / Q000235:genetics*; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D055785:Gene Knockdown Techniques; D020868:Gene Silencing; D064593:Heterografts; D006657:Histones / Q000378:metabolism; D006801:Humans; D061986:MCF-7 Cells; D051379:Mice; D041681:NIH 3T3 Cells; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism*; D015513:Oncogene Proteins / Q000235:genetics* / Q000378:metabolism; D063150:Polycomb Repressive Complex 1 / Q000235:genetics* / Q000378:metabolism; D000070584:Tripartite Motif Proteins; D044767:Ubiquitin-Protein Ligases
chemical_list: D006657:Histones; D009687:Nuclear Proteins; D015513:Oncogene Proteins; D000070584:Tripartite Motif Proteins; D063150:Polycomb Repressive Complex 1; C489841:RNF2 protein, human; C411745:TRIM37 protein, human; D044767:Ubiquitin-Protein Ligases