Phospho-MED1-enhanced UBE2C locus looping drives castration-resistant prostate cancer growth

Department of Molecular and Cellular Biochemistry and the Comprehensive Cancer Center, The Ohio State University College of Medicine, Columbus, OH, USA.
The EMBO Journal (Impact Factor: 10.43). 06/2011; 30(12):2405-19. DOI: 10.1038/emboj.2011.154
Source: PubMed

ABSTRACT The UBE2C oncogene is overexpressed in many types of solid tumours including the lethal castration-resistant prostate cancer (CRPC). The underlying mechanisms causing UBE2C gene overexpression in CRPC are not fully understood. Here, we show that CRPC-specific enhancers drive UBE2C overexpression in both AR-negative and -positive CRPC cells. We further show that co-activator MED1 recruitment to the UBE2C enhancers is required for long-range UBE2C enhancer/promoter interactions. Importantly, we find that the molecular mechanism underlying MED1-mediated chromatin looping involves PI3K/AKT phosphorylated MED1-mediated recruitment of FoxA1, RNA polymerase II and TATA binding protein and their subsequent interactions at the UBE2C locus. MED1 phosphorylation leads to UBE2C locus looping, UBE2C gene expression and cell growth. Our results not only define a causal role of a post-translational modification (phosphorylation) of a co-activator (MED1) in forming or sustaining an active chromatin structure, but also suggest that development of specific therapies for CRPC should take account of targeting phosphorylated MED1.

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    • "miR-96 expression was also associated with BCR, indicating its potential role as a prognostic biomarker. Notably, negative modulation of miR-205 in recurrent samples was confirmed also by Hulf et al. [55] who also demonstrated that this microRNA can impair cell viability of cancer cells through modulation of MED1 which has been correlated with castration-resistance acquisition [56]. Due to the high number of studies demonstrating the downregulation of miR-205 in patient-derived samples, the role of miR-205 in PCa biology has been further investigated in basic research, and recent reports demonstrated that this microRNA exerts its tumor-suppressive functions directly inhibiting the expression of the AR and its downstream signaling cascade, c-SRC oncogene and the antiapoptotic Bcl-2 protein [57] [58] [59] [60]. "
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    BioMed Research International 09/2014; 2014:146170. DOI:10.1155/2014/146170 · 2.71 Impact Factor
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    • "Therefore, it is plausible to presume that a looping model is the mechanism by which AR can regulate its targets from afar. In fact, this model has been proven to be true through 3C-based assays, which demonstrated that distal AR enhancer regions form long-range physical contacts with transcription start sites of AR-regulated genes, such as PSA and TMPRSS2,72,73 as well as UBE2C, which is a critical enzyme involved in promoting growth of castration-resistant prostate cancer.67,74 "
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    The Application of Clinical Genetics 05/2014; 7:81-91. DOI:10.2147/TACG.S35598
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    • "To assess the mechanism by which these pioneer factors contribute to chromatin loop formation and maintenance, we performed MED1 ChIP at the ABCC4 enhancer following siControl, siGATA2 and siFoxA1 transfection. Our results support previous findings that FoxA1 functions in the recruitment of MED1 to distal regulatory elements (37), as FoxA1 knockdown precipitated a significant reduction in MED1 occupancy. Importantly, siGATA2 transfection produced similar results, revealing that GATA2 also functions in the basal recruitment of chromatin loop-forming activities (Figure 6C). "
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    ABSTRACT: In prostate cancer, androgen receptor (AR) binding and androgen-responsive gene expression are defined by hormone-independent binding patterns of the pioneer factors FoxA1 and GATA2. Insufficient evidence of the mechanisms by which GATA2 contributes to this process precludes complete understanding of a key determinant of tissue-specific AR activity. Our observations suggest that GATA2 facilitates androgen-responsive gene expression by three distinct modes of action. By occupying novel binding sites within the AR gene locus, GATA2 positively regulates AR expression before and after androgen stimulation. Additionally, GATA2 engages AR target gene enhancers prior to hormone stimulation, producing an active and accessible chromatin environment via recruitment of the histone acetyltransferase p300. Finally, GATA2 functions in establishing and/or sustaining basal locus looping by recruiting the Mediator subunit MED1 in the absence of androgen. These mechanisms may contribute to the generally positive role of GATA2 in defining AR genome-wide binding patterns that determine androgen-responsive gene expression profiles. We also find that GATA2 and FoxA1 exhibit both independent and codependent co-occupancy of AR target gene enhancers. Identifying these determinants of AR transcriptional activity may provide a foundation for the development of future prostate cancer therapeutics that target pioneer factor function.
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