NKX3-1, an androgen-regulated homeobox gene, is located on the short arm of chromosome 8. It is a transcription factor and the first known prostate epithelium-specific marker, playing crucial roles in the development of the testes and prostate. Acting as a pioneer factor, it interacts with chromatin at enhancers to integrate androgen-regulated signalling [1,2]. It also has functions in protecting from oxidative stress and is regarded as a prostate-specific tumor suppressor [2,3]. Gene knockout models, such as the Nkx3.1 knockout rat model, can be used to further explore its functions [6].

In prostate cancer, decreased NKX3-1 protein expression is common. Post-translational modifications at multiple sites by different protein kinases play a vital role in regulating its stability and levels in prostate epithelial cells [3]. LIMK2 can directly phosphorylate NKX3-1, leading to its degradation, which promotes oncogenicity in castration-resistant prostate cancer (CRPC) cells both in vitro and in vivo. Also, NKX3-1 downregulates AR transcription and inhibits AKT signaling [4]. Moreover, NKX3-1 suppresses prostate cancer initiation by protecting mitochondria from oxidative stress, regulating transcription of mitochondrial-encoded electron transport chain genes [5].

In conclusion, NKX3-1 is essential for prostate development, maintenance of normal prostate secretory function, and acts as a tumor suppressor in the prostate. Studies using knockout models have revealed its role in processes like prostate cancer initiation, progression, and CRPC development, providing insights into the molecular mechanisms underlying these disease conditions [3,4,5,6].

References:

1. Antao, Ainsley Mike, Ramakrishna, Suresh, Kim, Kye-Seong. . The Role of Nkx3.1 in Cancers and Stemness. In International journal of stem cells, 14, 168-179. doi:10.15283/ijsc20121. https://pubmed.ncbi.nlm.nih.gov/33632988/

2. Griffin, Jon, Chen, Yuqing, Catto, James W F, El-Khamisy, Sherif. 2022. Gene of the month: NKX3.1. In Journal of clinical pathology, 75, 361-364. doi:10.1136/jclinpath-2021-208073. https://pubmed.ncbi.nlm.nih.gov/34996754/

3. Padmanabhan, Achuth, Rao, Varsha, De Marzo, Angelo M, Bieberich, Charles J. 2016. Regulating NKX3.1 stability and function: Post-translational modifications and structural determinants. In The Prostate, 76, 523-33. doi:10.1002/pros.23144. https://pubmed.ncbi.nlm.nih.gov/26841725/

4. Sooreshjani, Moloud A, Nikhil, Kumar, Kamra, Mohini, Kumar, Dinesh, Shah, Kavita. 2021. LIMK2-NKX3.1 Engagement Promotes Castration-Resistant Prostate Cancer. In Cancers, 13, . doi:10.3390/cancers13102324. https://pubmed.ncbi.nlm.nih.gov/34066036/

5. Papachristodoulou, Alexandros, Rodriguez-Calero, Antonio, Panja, Sukanya, Dutta, Aditya, Abate-Shen, Cory. 2021. NKX3.1 Localization to Mitochondria Suppresses Prostate Cancer Initiation. In Cancer discovery, 11, 2316-2333. doi:10.1158/2159-8290.CD-20-1765. https://pubmed.ncbi.nlm.nih.gov/33893149/

6. Lee, Ji Min, Kim, Ukjin, Yang, Hyokyung, Yamamoto, Takashi, Park, Jae-Hak. 2020. TALEN-mediated generation of Nkx3.1 knockout rat model. In The Prostate, 81, 182-193. doi:10.1002/pros.24095. https://pubmed.ncbi.nlm.nih.gov/33368416/