Please use this identifier to cite or link to this item: http://scholarbank.nus.edu.sg/handle/10635/29947
Title: NKX3-1, A NOVEL COFACTOR OF AR, PROMOTES PROSTATE CANCER SURVIVAL VIA RAB3B GTPASE-MEDIATED SIGNALING
Authors: TAN PECK YEAN
Keywords: NKX3-1, RAB3B, Prostate cancer cell survival
Issue Date: 9-Jun-2011
Source: TAN PECK YEAN (2011-06-09). NKX3-1, A NOVEL COFACTOR OF AR, PROMOTES PROSTATE CANCER SURVIVAL VIA RAB3B GTPASE-MEDIATED SIGNALING. ScholarBank@NUS Repository.
Abstract: A defective androgen receptor (AR) transcriptional network culminates in the development and progression of prostate tumorigenesis and the co-regulators of AR are likely to contribute to this malignancy. To elucidate the intricate relationship between AR and other co-factors, it is of importance to profile the locations of AR on the chromatin upon androgen stimulation. From our genome-wide analysis, we noticed the enrichment of NKX homeodomain (HD) transcription factor family motif within our AR binding sites (ARBS). HD proteins are initially thought to be only essential for organogenesis and cell fate specification during embryogenesis, but later suggested to drive human cancers. NKX3-1, which is the first known marker for prostate epithelial differentiation, was long postulated to be a prostate-specific tumor suppressor but the underlying mechanism still remains relatively unknown. Therefore, we sought to dissect the transcriptional role of NKX3-1 in the AR-mediated transcription in prostate cancer (PCa). From our NKX3-1 binding profile, we observed strong overlap with AR binding in response to androgen signaling. In addition to its collaborative transcriptional role at several androgen-dependent PCa model genes such as PSA, TMPRSS2 and FKBP5, our study also suggests NKX3-1 regulates AR in a feed-forward manner. Integrative analysis of Oncomine molecular concepts further substantiates the importance of AR and NKX3-1 co-regulated genes in prostate carcinoma (PCA). From our transcriptomic profiling and Gene Ontology (GO) analysis, we observed that these co-regulated genes are involved in `protein trafficking¿ processes, which are mandatory in the integration of oncogenic signaling pathways. Interestingly, we found that NKX3-1 works synergistically with AR and FoxA1 to co-regulate several members of the RAB GTPase family of secretory proteins. In particular, we demonstrated that these three factors could promote PCa cell survival through activation of RAB3B, which has been shown to be PCA-specific. Collectively, our study has provided important insights into the hierarchical transcriptional regulatory network established between AR and NKX3-1 and sought to elucidate the critical genetic-molecular-phenotypic paradigm in androgen-dependent PCa.
URI: http://scholarbank.nus.edu.sg/handle/10635/29947
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