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.
Science. 2016 Jun 24;352(6293):1576-80. doi: 10.1126/science.aad9512.
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.
NKX3.1 同源盒基因在前列腺分化和前列腺癌中发挥着重要作用。我们发现，在小鼠前列腺中，NKX3.1 的功能丧失会导致与前列腺分化至关重要的基因下调，同时导致通常不在前列腺中表达的基因上调。相反，在其他完全分化的非前列腺小鼠上皮（精囊）中，NKX3.1 的功能获得足以使肾脏移植物中的细胞重新特化为前列腺。在人类前列腺细胞中，这些活性需要 NKX3.1 通过同源域与 G9a 组蛋白甲基转移酶相互作用，并通过激活靶基因（如 UTY（KDM6c），UTX（KDM6a）的雄性特异性同源基因）来介导。我们提出，NKX3.1-G9a-UTY 转录调控网络对于前列腺分化至关重要，我们推测这种网络的破坏会导致前列腺癌。
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