Rnf126, or Ring finger protein 126, is an E3 ubiquitin ligase. Ubiquitination is a post-translational modification involved in proteolysis, protein-protein interaction, and signal transduction [3]. Rnf126 is associated with multiple cellular pathways such as DNA damage response (DDR), cell cycle regulation, and is important for maintaining genomic integrity [3,4]. It is also involved in the pathogenesis of many human diseases, especially various cancers [3,4].

In triple-negative breast cancer (TNBC), depletion of Rnf126 in both cells and mice leads to increased genomic instability and radiation sensitivity. Mechanistically, Rnf126 ubiquitinates MRE11, activating the ATR-CHK1 pathway for DNA damage repair (DDR), and thus conferring resistance of TNBC to radiotherapy [1]. In medulloblastoma (MB), deletion of Rnf126 in Group 3 MB (G3-MB) reduces the subcellular localization of ferroptosis suppressor protein 1 (FSP1) in the plasma membrane, increasing the CoQ/CoQH2 ratio. The Rnf126-FSP1-CoQ10 pathway suppresses phospholipid peroxidation and ferroptosis in vivo and in vitro [2]. In hepatocellular carcinoma (HCC), knockdown of Rnf126 in cells can reverse the promotion of cell proliferation, migration, invasion, and angiogenesis caused by overexpressed Rnf126. In mouse xenograft models, stable transformation of Rnf126 in Hep3B cells and subcutaneous injection into nude mice can effectively inhibit tumor growth and reduce lung metastasis [6]. In gastric cancer, Rnf126 gene silencing significantly inhibits the proliferation of gastric cancer cells, induces G1 phase arrest and increases the p21 protein level [5].

In conclusion, Rnf126 is a crucial E3 ubiquitin ligase involved in multiple biological processes, especially in DNA damage repair and cell proliferation regulation. Through gene knockout or knockdown studies in various cancer models (TNBC, G3-MB, HCC, gastric cancer), it has been shown that Rnf126 plays important roles in cancer development, providing potential diagnostic and therapeutic targets for these cancers.

References:

1. Liu, Wenjing, Zheng, Min, Zhang, Rou, Jiang, Dewei, Chen, Ceshi. 2022. RNF126-Mediated MRE11 Ubiquitination Activates the DNA Damage Response and Confers Resistance of Triple-Negative Breast Cancer to Radiotherapy. In Advanced science (Weinheim, Baden-Wurttemberg, Germany), 10, e2203884. doi:10.1002/advs.202203884. https://pubmed.ncbi.nlm.nih.gov/36563124/

2. Xie, Wanqun, Wang, Jiajia, Tian, Shuaiwei, Jiang, Feng, Ma, Jie. 2024. RNF126-mediated ubiquitination of FSP1 affects its subcellular localization and ferroptosis. In Oncogene, 43, 1463-1475. doi:10.1038/s41388-024-02949-x. https://pubmed.ncbi.nlm.nih.gov/38514855/

3. Chang, Hae Ryung. 2023. RNF126, 168 and CUL1: The Potential Utilization of Multi-Functional E3 Ubiquitin Ligases in Genome Maintenance for Cancer Therapy. In Biomedicines, 11, . doi:10.3390/biomedicines11092527. https://pubmed.ncbi.nlm.nih.gov/37760968/

4. Zhang, Rou, Liu, Wenjin, Sun, Jian, Kong, Yanjie, Chen, Ceshi. 2020. Roles of RNF126 and BCA2 E3 ubiquitin ligases in DNA damage repair signaling and targeted cancer therapy. In Pharmacological research, 155, 104748. doi:10.1016/j.phrs.2020.104748. https://pubmed.ncbi.nlm.nih.gov/32147403/

5. Migita, Kazuhiro, Matsumoto, Sohei, Wakatsuki, Kohei, Miyao, Shintaro, Sho, Masayuki. . RNF126 as a Marker of Prognosis and Proliferation of Gastric Cancer. In Anticancer research, 40, 1367-1374. doi:10.21873/anticanres.14078. https://pubmed.ncbi.nlm.nih.gov/32132033/

6. Huang, Jie, Li, Yan, Zheng, Mengyao, Xu, Dingwei, Tian, Daguang. 2022. RNF126 contributes to stem cell-like properties and metastasis in hepatocellular carcinoma through ubiquitination and degradation of LKB1. In Human cell, 35, 1869-1884. doi:10.1007/s13577-022-00782-6. https://pubmed.ncbi.nlm.nih.gov/36068398/