TRIM37 is a new histone H2A ubiquitin ligase and breast cancer oncoprotein
Authors
Bhatnagar, SanchitaGazin, Claude
Chamberlain, Lynn
Ou, Jianhong
Zhu, Xiaochun
Tushir, Jogender S.
Virbasius, Ching-Man A.
Lin, Ling
Zhu, Lihua Julie
Wajapeyee, Narendra
Green, Michael R.
Document Type
Journal ArticlePublication Date
2014-12-04Keywords
AnimalsBreast Neoplasms
Female
Gene Expression Profiling
*Gene Expression Regulation, Neoplastic
Gene Knockdown Techniques
Gene Silencing
Heterografts
Histones
Humans
MCF-7 Cells
Mice
NIH 3T3 Cells
Nuclear Proteins
Oncogene Proteins
Polycomb Repressive Complex 1
Cancer Biology
Metadata
Show full item recordAbstract
The TRIM37 (also known as MUL) gene is located in the 17q23 chromosomal region, which is amplified in up to approximately 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.Source
Nature. 2014 Dec 4;516(7529):116-20. doi: 10.1038/nature13955. Epub 2014 Nov 24. Link to article on publisher's siteDOI
10.1038/nature13955Permanent Link to this Item
http://hdl.handle.net/20.500.14038/36540PubMed ID
25470042Related Resources
Link to Article in PubMedae974a485f413a2113503eed53cd6c53
10.1038/nature13955