title: Integration of regulatory networks by NKX3-1 promotes androgen-dependent prostate cancer survival.
abstract: 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.
authors.affiliation: Cancer Biology and Pharmacology, Genome Institute of Singapore, Agency for Science, Technology and Research, Singapore, Singapore.
authors.forename: Peck Yean
authors.initials: PY
authors.lastname: Tan
authors.forename: Cheng Wei
authors.initials: CW
authors.lastname: Chang
authors.forename: Kern Rei
authors.initials: KR
authors.lastname: Chng
authors.forename: K D Senali Abayratna
authors.initials: KD
authors.lastname: Wansa
authors.forename: Wing-Kin
authors.initials: WK
authors.lastname: Sung
authors.forename: Edwin
authors.initials: E
authors.lastname: Cheung
mesh_terms: D000728:Androgens / Q000378:metabolism; D045744:Cell Line, Tumor; D002470:Cell Survival; D047369:Chromatin Immunoprecipitation; D015972:Gene Expression Regulation, Neoplastic; D053263:Gene Regulatory Networks; D051541:Hepatocyte Nuclear Factor 3-alpha / Q000378:metabolism; D018398:Homeodomain Proteins / Q000032:analysis / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D008297:Male; D011401:Promoter Regions, Genetic; D011467:Prostate / Q000378:metabolism / Q000473:pathology; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D011485:Protein Binding; D011944:Receptors, Androgen / Q000032:analysis / Q000235:genetics* / Q000378:metabolism; D014157:Transcription Factors / Q000032:analysis / Q000235:genetics* / Q000378:metabolism; D015533:Transcriptional Activation; D020692:rab3 GTP-Binding Proteins / Q000235:genetics
chemical_list: D000728:Androgens; C496499:FOXA1 protein, human; D051541:Hepatocyte Nuclear Factor 3-alpha; D018398:Homeodomain Proteins; C491178:NKX3-1 protein, human; D011944:Receptors, Androgen; D014157:Transcription Factors; C492131:RAB3B protein, human; D020692:rab3 GTP-Binding Proteins
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