NKX3-1 is a homeobox gene required for prostate tumor progression, but how it functions is unclear.
Herein, using ChIP-seq we show NKX3-1 co-localizes with the androgen receptor (AR) across the prostate cancer genome. We uncover 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 co-regulated genes include those found in the 'protein trafficking' process, which integrates oncogenic signaling pathways. Moreover, we demonstrate NKX3-1, AR and FoxA1 promote prostate cancer cell survival by directly up-regulating RAB3B, a member of the RAB GTPase family. Finally, we show RAB3B is over expressed in prostate cancer patients, suggesting RAB3B together with AR, FoxA1, and NKX3-1 are important regulators of prostate cancer progression. Collectively, our work highlight 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.
Tan PY, Chang CW, Chng KR, Wansa KD, Sung WK, Cheung E. Are you the author?
Reference: Mol Cell Biol. 2011 Nov 14. Epub ahead of print.