Alternative titles; symbols
HGNC Approved Gene Symbol: NKX3-1
Cytogenetic location: 8p21.2 Genomic coordinates (GRCh38): 8:23,678,693-23,682,938 (from NCBI)
The homeodomain-containing transcription factor NKX3-1 is a putative prostate tumor suppressor that is expressed in a largely prostate-specific and androgen-regulated manner. Loss of NKX3-1 protein expression is a common finding in human prostate carcinomas and prostatic intraepithelial neoplasia (summary by Abdulkadir et al., 2002).
Using a random cDNA sequencing approach, He et al. (1997) cloned a novel prostate-specific gene that encodes a homeobox-containing protein. The gene, which they symbolized NKX3.1, encodes a deduced 234-amino acid polypeptide with greatest homology to the Drosophila NK3 gene. Northern blot analysis showed that NKX3.1 had a uniquely restricted tissue expression pattern. The 3.5-kb NKX3.1 mRNA was abundant in the prostate, present at a lower level in the testis, and absent from all other tissues tested. He et al. (1997) detected NKX3.1 expression in a hormone-responsive, androgen receptor-positive prostate cancer cell line, but not in either of 2 androgen receptor-negative prostate cancer cell lines, or in 11 other cell lines of varied origin. Androgen stimulation markedly increased NKX3.1 expression in an androgen-dependent carcinoma line. The authors suggested that the NKX3.1 gene plays a role in androgen-driven differentiation of prostatic tissue and in the loss of that differentiation during the progression of prostate cancer.
Korkmaz et al. (2000) obtained a full-length NKX3-1 cDNA from a human prostate cDNA library. They identified 3 splice variants with deletions in the N-terminal region as well as a variant at position 137 in the homeobox domain. Fluorescent microscopy demonstrated restricted expression of GFP-NKX3-1 in the nucleus. Korkmaz et al. (2000) found that expression of Nkx3.1 decreased in a xenograft prostate tumor model after castration and removal of androgens.
Bieberich et al. (1996) cloned and characterized Nkx3.1, the mouse homolog of this gene.
By fluorescence in situ hybridization, He et al. (1997) mapped the NKX3.1 gene to human chromosome 8p21. He et al. (1997) stated that this chromosomal region frequently undergoes loss of heterozygosity during the progression of prostate cancer.
Wang et al. (2009) demonstrated that NKX3-1 marks a stem cell population that functions during prostate regeneration. Genetic lineage marking demonstrated that rare luminal cells that express NKX3-1 in the absence of testicular androgens (castration-resistant NKX3-1-expressing cells, or CARNs), are bipotential and can self-renew in vivo, and single-cell transplantation assays showed that CARNs can reconstitute prostate ducts in renal grafts. Functional assays of Nkx3-1 mutant mice in serial prostate regeneration suggested that NKX3-1 is required for stem cell maintenance. Furthermore, targeted deletion of the PTEN (601728) gene in CARNs resulted in rapid carcinoma formation after androgen-mediated regeneration. Wang et al. (2009) concluded that CARNs represent a new luminal stem cell population that is an efficient target for oncogenic transformation in prostate cancer.
Using tissue recombination assays, Dutta et al. (2016) showed that loss of function of Nkx3.1 in mouse prostate resulted in downregulation of genes essential for prostate differentiation and upregulation of genes not normally expressed in prostate. Gain of function of Nkx3.1 in fully differentiated nonprostate mouse epithelium was sufficient for respecification to prostate in grafts placed under the kidney capsule. In human prostate cells, these activities required interaction of NKX3.1 with G9A methyltransferase (EHMT2; 604599) via the NKX3.1 homeodomain and were mediated by activation of target genes such as UTY (400009). Dutta et al. (2016) proposed that the NKX3.1-EHMT2-UTY transcriptional regulatory network is essential for prostate differentiation and that disruption of such a network predisposes to prostate cancer.
Abdulkadir et al. (2002) found that conditional deletion of one or both alleles of Nkx3.1 in transgenic mice led to the development of preinvasive lesions resembling human prostatic intraepithelial neoplasia.
Abdulkadir, S. A., Magee, J. A., Peters, T. J., Kaleem, Z., Naughton, C. K., Humphrey, P. A., Milbrandt, J. Conditional loss of Nkx3.1 in adult mice induces prostatic intraepithelial neoplasia. Molec. Cell. Biol. 22: 1495-1503, 2002. [PubMed: 11839815] [Full Text: https://doi.org/10.1128/MCB.22.5.1495-1503.2002]
Bieberich, C. J., Fujita, K., He, W. W., Jay, G. Prostate-specific and androgen-dependent expression of a novel homeobox gene. J. Biol. Chem. 271: 31779-31782, 1996. [PubMed: 8943214] [Full Text: https://doi.org/10.1074/jbc.271.50.31779]
Dutta, A., Le Magnen, C., Mitrofanova, A., Ouyang, X., Califano, A., Abate-Shen, C. Identification of an NKX3.1-G9a-UTY transcriptional regulatory network that controls prostate differentiation. Science 352: 1576-1580, 2016. [PubMed: 27339988] [Full Text: https://doi.org/10.1126/science.aad9512]
He, W. W., Sciavolino, P. J., Wing, J., Augustus, M., Hudson, P., Meissner, P. S., Curtis, R. T., Shell, B. K., Bostwick, D. G., Tindall, D. J., Gelmann, E. P., Abate-Shen, C., Carter, K. C. A novel human prostate-specific, androgen-regulated homeobox gene (NKX3.1) that maps to 8p21, a region frequently deleted in prostate cancer. Genomics 43: 69-77, 1997. [PubMed: 9226374] [Full Text: https://doi.org/10.1006/geno.1997.4715]
Korkmaz, K. S., Korkmaz, C. G, Ragnhildstveit, E., Kizildag, S., Pretlow, T. G., Saatcioglu, F. Full-length cDNA sequence and genomic organization of human NKX3A--alternative forms and regulation by both androgens and estrogens. Gene 260: 25-36, 2000. [PubMed: 11137288] [Full Text: https://doi.org/10.1016/s0378-1119(00)00453-4]
Wang, X., Kruithof-de Julio, M., Economides, K. D., Walker, D., Yu, H., Halili, M. V., Hu, Y.-P., Price, S. M., Abate-Shen, C., Shen, M. M. A luminal epithelial stem cell that is a cell of origin for prostate cancer. Nature 461: 495-500, 2009. [PubMed: 19741607] [Full Text: https://doi.org/10.1038/nature08361]