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: 10.75). 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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    • "The predicted transcription factors binding sites at the UBE2C promoter have been identified, including binding sites for C-Rel, Pax-2, Pax-2a, CP1A, CP1C (GeneCard: GC20P044442), NF-1, SRF, TGIF, Meis-1 and c-Myc (Hao et al., 2012). UBE2C can be an androgen receptor target gene in prostate cancer cells and is responsive to hyperphosphorylated MED1 (androgen receptor co-activator mediator-1) in androgen receptor negative prostate cancer cells (Chen et al., 2011). UBE2C expression can also be induced by the estrogen receptor in breast cancer cells (Wang et al., 2013). "
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    • "In agreement with these findings, the Wang group has shown that expression of the androgen receptor oncogene target UBE2C was sensitive to MED1 phosphorylation at T1032 (Chen et al., 2011). MED1 phosphorylation was linked to more stable and active PICs; furthermore, UBE2C expression correlated with chromatin loop formation (linking the enhancer and promoter), and this architectural change was dependent on MED1 phosphorylation by the PI3K/AKT pathway. "
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