Integration of regulatory networks by NKX3-1 promotes androgen-dependent prostate cancer survival

• Main Authors: Tan, Peck Yean, Chang, Cheng Wei, Chng, Kern Rei, Wansa, K. D. Senali Abayratna, Sung, Wing-Kin, Cheung, Edwin
• Other Authors: School of Biological Sciences
• Format: Article
• Language: English
• Published: 2013
• Subjects: DRNTU::Science::Biological sciences
• Online Access: https://hdl.handle.net/10356/102012; http://hdl.handle.net/10220/11164
• Institution: Nanyang Technological University

The NKX3-1 gene is a homeobox gene required for prostate tumor progression, but how it functions is unclear. Here, using chromatin immunoprecipitation coupled to massively parallel sequencing (ChIP-seq) we showed that NKX3-1 colocalizes with the androgen receptor (AR) across the prostate cancer genome. We uncovered two distinct mechanisms by which NKX3-1 controls the AR transcriptional network in prostate cancer. First, NKX3-1 and AR directly regulate each other in a feed-forward regulatory loop. Second, NKX3-1 collaborates with AR and FoxA1 to mediate genes in advanced and recurrent prostate carcinoma. NKX3-1- and AR-coregulated genes include those found in the “protein trafficking” process, which integrates oncogenic signaling pathways. Moreover, we demonstrate that NKX3-1, AR, and FoxA1 promote prostate cancer cell survival by directly upregulating RAB3B, a member of the RAB GTPase family. Finally, we show that RAB3B is overexpressed in prostate cancer patients, suggesting that RAB3B together with AR, FoxA1, and NKX3-1 are important regulators of prostate cancer progression. Collectively, our work highlights a novel hierarchical transcriptional regulatory network between NKX3-1, AR, and the RAB GTPase signaling pathway that is critical for the genetic-molecular-phenotypic paradigm in androgen-dependent prostate cancer.