NKX3-1 (NK3 homeobox 1)

2009-03-01   Liang-Nian Song , Edward P Gelmann 

Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY 10032, USA




Atlas Image
The gene for NKX3-1 comprises two exons of 334 and 2947 bp, respectively. The length of the intron is 964 bp. Positions of start and stop codons are indicated.


The gene has two exons and one intron.


Transcription takes place in a centromere --> telomere orientation. The length of the processed mRNA is about 3200 bp.


Not known.


Atlas Image
NKX3-1 contains two exons encoding a 234-amino acid protein including a homeodomain (grey).


234 amino acids; 35-38 kDa, contains one N-terminal domain (residues 1-123), one homeodomain (residues 124-183), and one C-terminal domain (residues 184-234).


Expression is restricted to the adult murine prostate and bulbourethral gland. During early murine embryogenesis NKX3-1 expression has also been detected in developing somites and testes. In the adult human expression is seen in prostate epithelium, testis, ureter, and pulmonary bronchial mucous glands.




Binds to DNA to suppress transcription. Interacts with transcription factors, e.g. serum response factor, to enhance transcriptional activation. Binds to and potentiates topoisomerase I DNA resolving activity. Acts as prostate tumor suppressor.


Homeodomain protein with membership of the NKX family.



Twenty-one germ-line variants have been identified in 159 probands of hereditary prostate cancer families. These variants were linked to prostate cancer risk in hereditary prostate cancer families. For example, the C154T (11% of the population) polymorphism mutation is associated with prostatic enlargement and prostate cancer risk. A T164A mutations in one family cosegregates with prostate cancer in three affected brothers. For a more complete list of identified mutations, please visit http://cancerres.aacrjournals.org/cgi/content/full/66/1/69.



Implicated in

Entity name
Prostate Cancer
Prostate cancer is the most commonly diagnosed cancer in American men and the second leading cause of cancer-related deaths. Prostate cancer predominantly occurs in the peripheral zone of the human prostate, with roughly 5 to 10% of cases found in the central zone. Disease development involves the temporal and spatial loss of the basal epithelial compartment accompanied by increased proliferation and dedifferentiation of the luminal (secretory) epithelial cells. Prostate cancer is a slow developing disease that is typically found in men greater than 60 years of age and incidence increases with increasing age.
PSA test combined with digital-rectal exams are used to screen for the presence of disease. If the digital-rectal exams are positive, additional tests including needle core biopsies are taken to assess disease stage and grade. Patients with localized, prostate-restricted disease are theoretically curable with complete removal of the prostate (radical prostatectomy). Patients with extra-prostatic disease are treated with hormone (androgen ablation) therapy, radiation, and/or antiandrogens; however, no curative treatments are available for nonorgan confined, metastatic disease.
Various forms of aneuploidy.
Nkx3.1 plays an essential role in normal murine prostate development. Loss of function of Nkx3.1 leads to defects in prostatic protein secretions and in ductal morphogenesis. Loss-of-function of Nkx3.1 also contributes to prostate carcinogenesis. For example, Nkx3.1 mutant mice develop prostatic dysplasia. Nkx3.1 loss potentiates prostate carcinogenesis in a Pten+/- background. Furthermore, by a variety of mechanisms NKX3.1 expression is reduced in noninvasive and early stage human prostate cancer, suggesting that its decreased expression is one of the earliest steps in the majority of human prostate cancers.


Pubmed IDLast YearTitleAuthors
185577592008Integrating differentiation and cancer: the Nkx3.1 homeobox gene in prostate organogenesis and carcinogenesis.Abate-Shen C et al
118398152002Conditional loss of Nkx3.1 in adult mice induces prostatic intraepithelial neoplasia.Abdulkadir SA et al
157349992005Deletion, methylation, and expression of the NKX3.1 suppressor gene in primary human prostate cancer.Asatiani E et al
171081052006Decreased NKX3.1 protein expression in focal prostatic atrophy, prostatic intraepithelial neoplasia, and adenocarcinoma: association with gleason score and chromosome 8p deletion.Bethel CR et al
102156241999Roles for Nkx3.1 in prostate development and cancer.Bhatia-Gaur R et al
110855352000Loss of NKX3.1 expression in human prostate cancers correlates with tumor progression.Bowen C et al
172347522007NKX3.1 homeodomain protein binds to topoisomerase I and enhances its activity.Bowen C et al
126610362003Expression of NKX3.1 in normal and malignant tissues.Gelmann EP et al
92263741997A novel human prostate-specific, androgen-regulated homeobox gene (NKX3.1) that maps to 8p21, a region frequently deleted in prostate cancer.He WW et al
187941252008Nkx3-1 and LEF-1 function as transcriptional inhibitors of estrogen receptor activity.Holmes KA et al
168148062006Physical and functional interactions between the prostate suppressor homeoprotein NKX3.1 and serum response factor.Ju JH et al
118544552002Cooperativity of Nkx3.1 and Pten loss of function in a mouse model of prostate carcinogenesis.Kim MJ et al
153110572004Analysis of androgen regulated homeobox gene NKX3.1 during prostate carcinogenesis.Korkmaz CG et al
111372882000Full-length cDNA sequence and genomic organization of human NKX3A - alternative forms and regulation by both androgens and estrogens.Korkmaz KS et al
165817762006NKX3.1 is regulated by protein kinase CK2 in prostate tumor cells.Li X et al
126765852003Haploinsufficiency at the Nkx3.1 locus. A paradigm for stochastic, dosage-sensitive gene regulation during tumor initiation.Magee JA et al
187574022008Inflammatory cytokines induce phosphorylation and ubiquitination of prostate suppressor protein NKX3.1.Markowski MC et al
176021652007Haploinsufficient prostate tumor suppression by Nkx3.1: a role for chromatin accessibility in dosage-sensitive gene regulation.Mogal AP et al
112577112001Expression studies and mutational analysis of the androgen regulated homeobox gene NKX3.1 in benign and malignant prostate epithelium.Ornstein DK et al
95376021998Isolation and androgen regulation of the human homeobox cDNA, NKX3.1.Prescott JL et al
164425982006Effect of homeodomain protein NKX3.1 R52C polymorphism on prostate gland size.Rodriguez Ortner E et al
109064592000Targeted disruption of the Nkx3.1 gene in mice results in morphogenetic defects of minor salivary glands: parallels to glandular duct morphogenesis in prostate.Schneider A et al
91425021997Tissue-specific expression of murine Nkx3.1 in the male urogenital system.Sciavolino PJ et al
146488542003Roles of the Nkx3.1 homeobox gene in prostate organogenesis and carcinogenesis.Shen MM et al
162019672006Nkx3.1 binds and negatively regulates the transcriptional activity of Sp-family members in prostate-derived cells.Simmons SO et al
108713722000DNA-binding sequence of the human prostate-specific homeodomain protein NKX3.1.Steadman DJ et al
110023442000Nkx3.1, a murine homolog of Ddrosophila bagpipe, regulates epithelial ductal branching and proliferation of the prostate and palatine glands.Tanaka M et al
104153591999Expression of the Nkx3.1 homobox gene during pre and postnatal development.Tanaka M et al
93775511997Coding region of NKX3.1, a prostate-specific homeobox gene on 8p21, is not mutated in human prostate cancers.Voeller HJ et al
106880342000Expression profile of an androgen regulated prostate specific homeobox gene NKX3.1 in primary prostate cancer.Xu LL et al
182967352008Structural and functional analysis of domains mediating interaction between the bagpipe homologue, Nkx3.1 and serum response factor.Zhang Y et al
163972182006Germ-line mutation of NKX3.1 cosegregates with hereditary prostate cancer and alters the homeodomain structure and function.Zheng SL et al

Other Information

Locus ID:

NCBI: 4824
MIM: 602041
HGNC: 7838
Ensembl: ENSG00000167034


dbSNP: 4824
ClinVar: 4824
TCGA: ENSG00000167034


Gene IDTranscript IDUniprot

Expression (GTEx)



PathwaySourceExternal ID
Prostate cancerKEGGko05215
Pathways in cancerKEGGhsa05200
Prostate cancerKEGGhsa05215

Protein levels (Protein atlas)

Not detected


Pubmed IDYearTitleCitations
197677532009Identification of seven new prostate cancer susceptibility loci through a genome-wide association study.225
166979572006NKX3.1 stabilizes p53, inhibits AKT activation, and blocks prostate cancer initiation caused by PTEN loss.81
220839572012Integration of regulatory networks by NKX3-1 promotes androgen-dependent prostate cancer survival.71
171081052006Decreased NKX3.1 protein expression in focal prostatic atrophy, prostatic intraepithelial neoplasia, and adenocarcinoma: association with gleason score and chromosome 8p deletion.64
204799322010ETS transcription factors control transcription of EZH2 and epigenetic silencing of the tumor suppressor gene Nkx3.1 in prostate cancer.55
157349992005Deletion, methylation, and expression of the NKX3.1 suppressor gene in primary human prostate cancer.50
205643192010Prostate cancer risk-associated variants reported from genome-wide association studies: meta-analysis and their contribution to genetic Variation.36
203639132010Loss of Nkx3.1 expression in bacterial prostatitis: a potential link between inflammation and neoplasia.34
146488542003Roles of the Nkx3.1 homeobox gene in prostate organogenesis and carcinogenesis.31
208554952010NKX3.1 is a direct TAL1 target gene that mediates proliferation of TAL1-expressing human T cell acute lymphoblastic leukemia.29


Liang-Nian Song ; Edward P Gelmann

NKX3-1 (NK3 homeobox 1)

Atlas Genet Cytogenet Oncol Haematol. 2009-03-01

Online version: http://atlasgeneticsoncology.org/gene/41541/nkx3-1-(nk3-homeobox-1)