Smc4, short for Structural Maintenance of Chromosome 4, is a member of the ATPase family of chromosomes. Its most well-reported function is in the compression and dissociation of sister chromatids, along with involvement in DNA damage repair, DNA recombination, and genome transcription. It also plays a role in processes like RNA splicing, DNA metabolism, cell adhesion, and extracellular matrix in embryonic cell division cycles. Additionally, it is a positive regulator of the inflammatory innate immune response [2].

SMC4 attenuation in colorectal cancer cells promotes the expression of certain glycolysis enzymes, increases lactate production, suppresses PGAM1, and ultimately leads to chemotherapy insensitivity and low cell proliferation [1]. In endometrial cancer, SMC4 knockdown represses cell proliferation and promotes apoptosis by regulating FoxO1 activity [6]. In hepatoma cells, SMC4 promotes autophagy to enhance chemoresistance, and its knockdown can restore 5-FU sensitivity [4,7]. Also, SMC4 is associated with prognosis and immune infiltration in sarcoma, and its high expression is related to poor outcomes in multiple cancers including gastric, breast, liver, and ovarian cancer [3]. In colon adenocarcinoma, SMC4 is correlated with poor prognosis, proliferation, metastasis, and immune cell infiltrates [5].

In conclusion, Smc4 is crucial for chromosome-related functions and various cellular processes. Model-based research, especially loss-of-function experiments, has revealed its significant roles in cancer-related processes such as proliferation, chemotherapy resistance, and immune infiltration, highlighting its potential as a prognostic marker and therapeutic target in multiple cancer types.

References:

1. Sun, Xuedan, He, Lifang, Liu, Hong, Wu, Mian, Liu, Lianxin. 2023. The diapause-like colorectal cancer cells induced by SMC4 attenuation are characterized by low proliferation and chemotherapy insensitivity. In Cell metabolism, 35, 1563-1579.e8. doi:10.1016/j.cmet.2023.07.005. https://pubmed.ncbi.nlm.nih.gov/37543034/

2. Zhao, Zonglei, Wang, Xixiu, Ding, Yan, Cao, Xuefeng, Zhang, Xingyuan. 2023. SMC4, a novel tumor prognostic marker and potential tumor therapeutic target. In Frontiers in oncology, 13, 1117642. doi:10.3389/fonc.2023.1117642. https://pubmed.ncbi.nlm.nih.gov/37007153/

3. Jiang, Guangyao, Chen, Junjie, Li, Yan, Wu, Gen, Zhang, Yupeng. 2023. Association of SMC4 with prognosis and immune infiltration of sarcoma. In Aging, 15, 567-582. doi:10.18632/aging.204503. https://pubmed.ncbi.nlm.nih.gov/36719264/

4. Zhang, Shi-Ran, Li, Jie, Chen, Jing-Xiang, Fu, Hang-Wei, Zhou, Bo. . SMC4 enhances the chemoresistance of hepatoma cells by promoting autophagy. In Annals of translational medicine, 10, 1308. doi:10.21037/atm-22-3623. https://pubmed.ncbi.nlm.nih.gov/36660610/

5. Yang, Dawei, Cheng, Wenxin, Liu, Ying, Yang, Yang, Wang, Xinyue. . SMC4 serves as a potential marker for the diagnosis and prognosis of colon adenocarcinoma. In International journal of immunopathology and pharmacology, 38, 3946320241286565. doi:10.1177/03946320241286565. https://pubmed.ncbi.nlm.nih.gov/39423024/

6. Yan, Yani, Liu, Cong, Zhang, Jian, Pang, Shulan, Li, Xuefeng. 2021. SMC4 knockdown inhibits malignant biological behaviors of endometrial cancer cells by regulation of FoxO1 activity. In Archives of biochemistry and biophysics, 712, 109026. doi:10.1016/j.abb.2021.109026. https://pubmed.ncbi.nlm.nih.gov/34506757/

7. Zhou, Bo, Li, Jie, Wu, Shuai, Chen, Jingxiang, Chen, Geng. 2025. USP39/SMC4 promotes hepatoma cell proliferation and 5-FU resistance. In Scientific reports, 15, 8869. doi:10.1038/s41598-025-93029-x. https://pubmed.ncbi.nlm.nih.gov/40087331/