Journal
ONCOGENE
Volume 36, Issue 21, Pages 2991-3001Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/onc.2016.453
Keywords
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Funding
- CPRIT [RP110471]
- Gigli Family Endowed Scholarship of the UT-Graduate School of Biomedical Sciences at Houston, TX
- Laura and John Arnold Foundation
- Odyssey Program fellowship
- CPRIT Core Facility Support [RP120348]
- National Institutes of Health through MD Anderson's Cancer Center Support [CA016672]
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Histone methyl transferase EZH2 (Enhancer of Zeste Homolog 2) is generally associated with H3K27 methylation and gene silencing, as a member of the polycomb repressor 2 (PRC2) complex. Immunoprecipitation and mass spectrometry of the EZH2-protein interactome in estrogen receptor positive, breast cancer-derived MCF7 cells revealed EZH2 interactions with subunits of chromatin remodeler SWI/SNF complex and TRIM28, which formed a complex with EZH2 distinct from PRC2. Unexpectedly, transcriptome profiling showed that EZH2 primarily activates, rather than represses, transcription in MCF7 cells and with TRIM28 co-regulates a set of genes associated with stem cell maintenance and poor survival of breast cancer patients. TRIM28 depletion repressed EZH2 recruitment to chromatin and expression of this gene set, in parallel with decreased CD44(hi)/CD24(lo) mammosphere formation. Mammosphere formation, inhibited by EZH2 depletion, was rescued by ectopic expression of EZH2 but not by TRIM28 expression or by EZH2 mutated at the region (pre-SET domain) of TRIM28 interaction. These results support PRC2-independent functions of EZH2 and TRIM28 in activation of gene expression that promotes mammary stem cell enrichment and maintenance.
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