title: Identification of an NKX3.1-G9a-UTY transcriptional regulatory network that controls prostate differentiation.
abstract: 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.
authors.affiliation: Departments of Medicine and Urology, Institute of Cancer Genetics, Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, New York, NY 10032, USA.
authors.forename: Aditya
authors.initials: A
authors.lastname: Dutta
authors.affiliation: Departments of Medicine and Urology, Institute of Cancer Genetics, Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, New York, NY 10032, USA.
authors.forename: Clémentine
authors.initials: C
authors.lastname: Le Magnen
authors.affiliation: Department of Systems Biology, Columbia University Medical Center, New York, NY 10032, USA.
authors.forename: Antonina
authors.initials: A
authors.lastname: Mitrofanova
authors.affiliation: Department of Urology, Columbia University Medical Center, New York, NY 10032, USA.
authors.forename: Xuesong
authors.initials: X
authors.lastname: Ouyang
authors.affiliation: 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.
authors.forename: Andrea
authors.initials: A
authors.lastname: Califano
authors.affiliation: 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. cabateshen@columbia.edu.
authors.forename: Cory
authors.initials: C
authors.lastname: Abate-Shen
mesh_terms: D000818:Animals; D002460:Cell Line; D004847:Epithelial Cells; D055785:Gene Knockdown Techniques; D053263:Gene Regulatory Networks; D006649:Histocompatibility Antigens; D011495:Histone-Lysine N-Methyltransferase; D018398:Homeodomain Proteins; D006801:Humans; D016086:Lentivirus; D008297:Male; D051379:Mice; D015778:Minor Histocompatibility Antigens; D009687:Nuclear Proteins; D011467:Prostate; D051381:Rats; D014157:Transcription Factors
chemical_list: D006649:Histocompatibility Antigens; D018398:Homeodomain Proteins; D015778:Minor Histocompatibility Antigens; C491178:NKX3-1 protein, human; D009687:Nuclear Proteins; D014157:Transcription Factors; C484453:UTY protein, human; C445405:EHMT2 protein, human; D011495:Histone-Lysine N-Methyltransferase