Kcnn4, encoding the calcium-activated potassium channel KCa3.1, is a member of the potassium calcium-activated channel subfamily. It is involved in multiple biological processes, regulating calcium-related signaling pathways [2,3,5,6,7]. It has been shown to be associated with various physiological and pathological conditions, playing a role in immune cell function, cancer progression, and red blood cell-related processes [1,2,3,4,5,6,7,8,9,10]. Genetic models, such as gene knockout (KO) or conditional knockout (CKO) mouse models, are valuable tools for studying its functions.

In the context of disease, myeloid-specific deletion of PIEZO1/2 (upstream regulators of Kcnn4) protected mice from gouty arthritis, indicating that Kcnn4-mediated PIEZO-NLRP3 inflammasome activation is involved in auto-inflammatory diseases [1]. In pancreatic ductal adenocarcinoma (PDAC), knockdown of Kcnn4 attenuated cell growth, motility, and promoted apoptosis and cell cycle arrest [3]. In hepatocellular carcinoma, knockdown of Kcnn4 reduced migration, invasion, and proliferation abilities of HCC cells [5].

In conclusion, Kcnn4 is crucial in regulating multiple biological processes, especially in the context of inflammation and cancer. Model-based research, particularly KO/CKO mouse models, has revealed its role in diseases like gouty arthritis and various cancers, providing insights into potential therapeutic targets.

References:

1. Ran, Li, Ye, Tao, Erbs, Eric, Zhang, Zhirong, Ricci, Romeo. 2023. KCNN4 links PIEZO-dependent mechanotransduction to NLRP3 inflammasome activation. In Science immunology, 8, eadf4699. doi:10.1126/sciimmunol.adf4699. https://pubmed.ncbi.nlm.nih.gov/38134241/

2. Jiang, Shu-Heng, Zhu, Li-Li, Zhang, Man, Hou, Shangwei, Zhang, Zhi-Gang. 2019. GABRP regulates chemokine signalling, macrophage recruitment and tumour progression in pancreatic cancer through tuning KCNN4-mediated Ca2+ signalling in a GABA-independent manner. In Gut, 68, 1994-2006. doi:10.1136/gutjnl-2018-317479. https://pubmed.ncbi.nlm.nih.gov/30826748/

3. Mo, Xiao, Zhang, Cheng-Fei, Xu, Ping, Jia, Yu-Liang, Xia, Hong-Ping. 2021. KCNN4-mediated Ca2+/MET/AKT axis is promising for targeted therapy of pancreatic ductal adenocarcinoma. In Acta pharmacologica Sinica, 43, 735-746. doi:10.1038/s41401-021-00688-3. https://pubmed.ncbi.nlm.nih.gov/34183755/

4. Allegrini, B, Jedele, S, David Nguyen, L, Da Costa, L, Guizouarn, H. 2022. New KCNN4 Variants Associated With Anemia: Stomatocytosis Without Erythrocyte Dehydration. In Frontiers in physiology, 13, 918620. doi:10.3389/fphys.2022.918620. https://pubmed.ncbi.nlm.nih.gov/36003639/

5. Li, Qiu-Ting, Feng, Yi-Ming, Ke, Zun-Hui, Shi, Liang-Liang, Xiong, Zhi-Fan. 2019. KCNN4 promotes invasion and metastasis through the MAPK/ERK pathway in hepatocellular carcinoma. In Journal of investigative medicine : the official publication of the American Federation for Clinical Research, 68, 68-74. doi:10.1136/jim-2019-001073. https://pubmed.ncbi.nlm.nih.gov/31431469/

6. Lin, Peiyang, Li, Junjing, Ye, Fugui, Shao, Zhiming, Song, Chuangui. 2020. KCNN4 induces multiple chemoresistance in breast cancer by regulating BCL2A1. In American journal of cancer research, 10, 3302-3315. doi:. https://pubmed.ncbi.nlm.nih.gov/33163271/

7. Fan, Jing, Tian, Ruofei, Yang, Xiangmin, Chen, Zhinan, Li, Ling. 2022. KCNN4 Promotes the Stemness Potentials of Liver Cancer Stem Cells by Enhancing Glucose Metabolism. In International journal of molecular sciences, 23, . doi:10.3390/ijms23136958. https://pubmed.ncbi.nlm.nih.gov/35805963/

8. Lehrer, Steven, Rheinstein, Peter H. 2023. Increased KCNN4 Expression Is Correlated With Poor Survival in Lower Grade Glioma. In Cancer diagnosis & prognosis, 3, 428-432. doi:10.21873/cdp.10235. https://pubmed.ncbi.nlm.nih.gov/37405224/

9. Wen, Jialiang, Lin, Bangyi, Lin, Lizhi, Chen, Yizuo, Wang, Ouchen. 2020. KCNN4 is a diagnostic and prognostic biomarker that promotes papillary thyroid cancer progression. In Aging, 12, 16437-16456. doi:10.18632/aging.103710. https://pubmed.ncbi.nlm.nih.gov/32857728/

10. Chen, Shaohua, Su, Xiaotao, Mo, Zengnan. 2022. KCNN4 is a Potential Biomarker for Predicting Cancer Prognosis and an Essential Molecule that Remodels Various Components in the Tumor Microenvironment: A Pan-Cancer Study. In Frontiers in molecular biosciences, 9, 812815. doi:10.3389/fmolb.2022.812815. https://pubmed.ncbi.nlm.nih.gov/35720112/