Identification of an NKX3.1-G9a-UTY transcriptional regulatory network that controls prostate differentiation.

The NKX3.1 homeobox gene plays essential roles in prostate differentiation and prostate cancer. We show that loss of function of Nkx3.1 in mouse prostate results in down-regulation of genes that are essential for prostate differentiation, as well as up-regulation of genes that are not normally expressed in prostate. Conversely, gain of function of Nkx3.1 in an otherwise fully differentiated nonprostatic mouse epithelium (seminal vesicle) is sufficient for respecification to prostate in renal grafts in vivo. In human prostate cells, these activities require the interaction of NKX3.1 with the G9a histone methyltransferase via the homeodomain and are mediated by activation of target genes such as UTY (KDM6c), the male-specific paralog of UTX (KDM6a) We propose that an NKX3.1-G9a-UTY transcriptional regulatory network is essential for prostate differentiation, and we speculate that disruption of such a network predisposes to prostate cancer.

Science (New York, N.Y.). 2016 Jun 24 [Epub]

Aditya Dutta, Clémentine Le Magnen, Antonina Mitrofanova, Xuesong Ouyang, Andrea Califano, Cory Abate-Shen

Departments of Medicine and Urology, Institute of Cancer Genetics, Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, New York, NY 10032, USA., Departments of Medicine and Urology, Institute of Cancer Genetics, Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, New York, NY 10032, USA., Department of Systems Biology, Columbia University Medical Center, New York, NY 10032, USA., Department of Urology, Columbia University Medical Center, New York, NY 10032, USA., Departments of Systems Biology, Biomedical Informatics, and Biochemistry and Molecular Biophysics, Center for Computational Biology and Bioinformatics, Institute of Cancer Genetics, Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, New York, NY 10032, USA., Departments of Urology, Medicine, Systems Biology, and Pathology and Cell Biology, Institute of Cancer Genetics, Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, New York, NY 10032, USA. .