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
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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    • "The pGL4.10-E4TATA-Luc vectors with UBE2C Enhancer-1 (E-1) sequences and pBEC22 (a Renilla luciferase vector) were kindly provided by Dr. Qianben Wang [35]. Three ~400 bp regions in Enhancer 1 called E1-1, E1-2 and E1-3 were systematically subcloned into pGL4.10-E4TATA-Luc "
    [Show abstract] [Hide abstract] ABSTRACT: The appearance of constitutively active androgen receptor splice variants (AR-Vs) has been proposed as one of the causes of castration-resistant prostate cancer (CRPC). However, the underlying mechanism of AR-Vs in CRPC transcriptional regulation has not been defined. A distinct transcriptome enriched with cell cycle genes, e.g. UBE2C, has been associated with AR-Vs, which indicates the possibility of an altered transcriptional mechanism when compared to full-length wild-type AR (ARfl). Importantly, a recent study reported the critical role of p-MED1 in enhancing UBE2C expression through a locus looping pattern, which only occurs in CRPC but not in androgen-dependent prostate cancer (ADPC). To investigate the potential correlation between AR-V and MED1, in the present study we performed protein co-immunoprecipitation, chromatin immunoprecipitation, and cell proliferation assays and found that MED1 is necessary for ARv567es induced UBE2C up-regulation and subsequent prostate cancer cell growth. Furthermore, p-MED1 is bound to ARv567es independent of full-length AR; p-MED1 has higher recruitment to UBE2C promoter and enhancer regions in the presence of ARv567es. Our data indicate that p-MED1 serves as a key mediator in ARv567es induced gene expression and suggests a mechanism by which AR-Vs promote the development and progression of CRPC.
    Full-text · Article · Dec 2014 · Oncotarget
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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]. "
    [Show abstract] [Hide abstract] ABSTRACT: Prostate cancer (PCa) is one of the leading causes of cancer-related death in men. Despite considerable advances in prostate cancer early detection and clinical management, validation of new biomarkers able to predict the natural history of tumor progression is still necessary in order to reduce overtreatment and to guide therapeutic decisions. MicroRNAs are endogenous noncoding RNAs which offer a fast fine-tuning and energy-saving mechanism for posttranscriptional control of protein expression. Growing evidence indicate that these RNAs are able to regulate basic cell functions and their aberrant expression has been significantly correlated with cancer development. Therefore, detection of microRNAs in tumor tissues and body fluids represents a new tool for early diagnosis and patient prognosis prediction. In this review, we summarize current knowledge about microRNA deregulation in prostate cancer mainly focusing on the different clinical aspects of the disease. We also highlight the potential roles of microRNAs in PCa management, while also discussing several current challenges and needed future research.
    Full-text · Article · Sep 2014 · BioMed Research International
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    • "UBE2C is an anaphase-promoting complex/ cyclosome (APC/C)-specific E2 ubiquitin-conjugating enzyme, and upregulation of UBE2C inactivates the M phase cell cycle checkpoint [251]. Activation of UBE2C expression involves binding of the PI3K/AKT phosphorylated co-activator MED1 to the long range UBE2C enhancers, and chromatin looping through recruitment of FoxA1 [252]. Expression of UBE2C is driven by androgen receptor [85]. "
    [Show abstract] [Hide abstract] ABSTRACT: Prostate cancer co-opts a unique set of cellular pathways in its initiation and progression. The heterogeneity of prostate cancers is evident at earlier stages, and has led to rigorous efforts to stratify the localized prostate cancers, so that progression to advanced stages could be predicted based upon salient features of the early disease. The deregulated androgen receptor signaling is undeniably most important in the progression of the majority of prostate tumors. It is perhaps because of the primacy of the androgen receptor governed transcriptional program in prostate epithelium cells that once this program is corrupted, the consequences of the ensuing changes in activity are pleotropic and could contribute to malignancy in multiple ways. Following localized surgical and radiation therapies, 20-40% of patients will relapse and progress, and will be treated with androgen deprivation therapies. The successful development of the new agents that inhibit androgen signaling has changed the progression free survival in hormone resistant disease, but this has not changed the almost ubiquitous development of truly resistant phenotypes in advanced prostate cancer. This review summarizes the current understanding of the molecular pathways involved in localized and metastatic prostate cancer, with an emphasis on the clinical implications of the new knowledge.
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