STK39, serine/threonine kinase 39, is a key kinase involved in multiple biological processes. It participates in DNA damage response by phosphorylating H2A.X, promoting homologous recombination repair [1]. It is also associated with several signaling pathways such as PLK1/ERK, PI3K/AKT, which are crucial for cell proliferation, migration, and invasion in cancer progression [2,3]. Additionally, STK39 has been linked to blood pressure regulation as its polymorphism is associated with essential hypertension [5].

In cancer research, loss-of-function studies have shown significant impacts. Knockdown of STK39 in hepatocellular carcinoma (HCC) attenuated cell proliferation, migration, and invasion, and arrested the cell cycle in the G2/M phase while promoting apoptosis [2]. Similar effects were seen in cholangiocarcinoma, breast cancer, osteosarcoma, and pancreatic adenocarcinoma, where STK39 knockdown or inhibition suppressed tumor-promoting activities like cell proliferation, migration, invasion, and metastasis, and enhanced sensitivity to chemotherapy or PARP inhibitors [1,3,4,6]. In a mouse model of metabolic dysfunction-associated steatohepatitis (MASH), knockout of STK39 diminished immune cell infiltration in the liver, and treatment with a STK39 inhibitor prevented severe steatohepatitis by protecting the intestinal epithelial barrier [7].

In conclusion, STK39 plays essential roles in DNA damage repair, cell growth, and metastasis in cancer, as well as in blood pressure regulation and intestinal barrier protection in metabolic diseases. Loss-of-function studies, especially in mouse models, have revealed its significance in these biological processes and disease conditions, highlighting its potential as a therapeutic target for cancer and metabolic diseases.

References:

1. Xu, Yi, Li, Changying, Yin, Huan, Yi, Junlin, Deng, Min. . STK39-mediated amplification of γ-H2A.X promotes homologous recombination and contributes to PARP inhibitor resistance. In Nucleic acids research, 52, 13881-13895. doi:10.1093/nar/gkae1099. https://pubmed.ncbi.nlm.nih.gov/39588777/

2. Zhang, Chengfei, Wang, Xiaoming, Fang, Dan, Hui, Kam Man, Xia, Hongping. 2021. STK39 is a novel kinase contributing to the progression of hepatocellular carcinoma by the PLK1/ERK signaling pathway. In Theranostics, 11, 2108-2122. doi:10.7150/thno.48112. https://pubmed.ncbi.nlm.nih.gov/33500714/

3. Hao, Xiaopei, Zhang, Yao, Lu, Yiwei, Wu, Jindao, Wang, Xuehao. 2021. STK39 enhances the progression of Cholangiocarcinoma via PI3K/AKT pathway. In iScience, 24, 103223. doi:10.1016/j.isci.2021.103223. https://pubmed.ncbi.nlm.nih.gov/34746696/

4. Qiu, Zhaoping, Dong, Bo, Guo, Weijie, Evers, B Mark, Wu, Yadi. 2021. STK39 promotes breast cancer invasion and metastasis by increasing SNAI1 activity upon phosphorylation. In Theranostics, 11, 7658-7670. doi:10.7150/thno.62406. https://pubmed.ncbi.nlm.nih.gov/34335956/

5. Xi, Bo, Chen, Man, Chandak, Giriraj R, He, Juan, Mou, Si-Hua. 2013. STK39 polymorphism is associated with essential hypertension: a systematic review and meta-analysis. In PloS one, 8, e59584. doi:10.1371/journal.pone.0059584. https://pubmed.ncbi.nlm.nih.gov/23527223/

6. Huang, Tao, Zhou, Yuan, Cao, Yun, Zhou, Zhi-Hui, Hang, Dong-Hua. 2017. STK39, overexpressed in osteosarcoma, regulates osteosarcoma cell invasion and proliferation. In Oncology letters, 14, 4599-4604. doi:10.3892/ol.2017.6728. https://pubmed.ncbi.nlm.nih.gov/28943960/

7. Xu, Qing, Liu, Fei, Wu, Zhenru, Zhou, Yongjie, Shi, Yujun. 2024. Suppression of STK39 weakens the MASLD/MASH process by protecting the intestinal barrier. In Bioscience trends, 18, 289-302. doi:10.5582/bst.2024.01097. https://pubmed.ncbi.nlm.nih.gov/38925962/