Cstf2, also known as cleavage-stimulating factor subunit 2 or CSTF-64, is a protein that binds RNA and is essential for the cleavage and polyadenylation of mRNA. It is a component subunit of the cleavage stimulating factor (CSTF), located on the X chromosome and encoding 557 amino acids. This process is crucial for the 3'-end processing of pre-mRNAs, which impacts gene expression and various biological processes [2].

In multiple cancers, Cstf2 has been found to play significant roles. In pancreatic ductal adenocarcinoma (PDAC), it drives the formation of two m6A subtypes with different prognosis outcomes by co-transcriptionally regulating m6A installation [1]. In hepatocellular carcinoma (HCC), Cstf2 upregulation is frequent, and it supports hypoxia tolerance through m6A modification evasion of PGK1 to enhance glycolysis [3]. Also, Cstf2 promotes HCC carcinogenesis and progression via aerobic glycolysis, and its knockout inhibits HCC cell proliferation, migration, and invasion both in vitro and in vivo [4]. In glioblastoma, knockdown of Cstf2 induced cell apoptosis, as it unstabilized the mRNA of the BAD protein by shortening its 3' UTR [5].

In conclusion, Cstf2 is vital for mRNA processing and has a profound impact on cancer development. Gene knockout or knockdown studies in cell lines and animal models, especially in cancers like PDAC, HCC, and glioblastoma, have revealed its role in promoting tumor growth, metastasis, and immune evasion, highlighting its potential as a biomarker and therapeutic target for these diseases.

References:

1. Zheng, Yanfen, Li, Xingyang, Deng, Shuang, Zhang, Jialiang, Zuo, Zhixiang. 2023. CSTF2 mediated mRNA N6-methyladenosine modification drives pancreatic ductal adenocarcinoma m6A subtypes. In Nature communications, 14, 6334. doi:10.1038/s41467-023-41861-y. https://pubmed.ncbi.nlm.nih.gov/37816727/

2. Ding, Jiaxiang, Su, Yue, Liu, Youru, Zhou, Huan, Li, Hongtao. 2024. The role of CSTF2 in cancer: from technology to clinical application. In Cell cycle (Georgetown, Tex.), 22, 2622-2636. doi:10.1080/15384101.2023.2299624. https://pubmed.ncbi.nlm.nih.gov/38166492/

3. Zhang, Qiangnu, Zhang, Yusen, Fu, Chuli, Yan, Guang-Rong, Liu, Liping. . CSTF2 Supports Hypoxia Tolerance in Hepatocellular Carcinoma by Enabling m6A Modification Evasion of PGK1 to Enhance Glycolysis. In Cancer research, 85, 515-534. doi:10.1158/0008-5472.CAN-24-2283. https://pubmed.ncbi.nlm.nih.gov/39514400/

4. Chen, Zhimin, Hao, Weijie, Tang, Jingzhi, Gao, Wei-Qiang, Xu, Huiming. 2022. CSTF2 Promotes Hepatocarcinogenesis and Hepatocellular Carcinoma Progression via Aerobic Glycolysis. In Frontiers in oncology, 12, 897804. doi:10.3389/fonc.2022.897804. https://pubmed.ncbi.nlm.nih.gov/35875122/

5. Xu, Yang, Yuan, Fanen, Sun, Qian, Liu, Baohui, Chen, Qianxue. 2022. The RNA-binding protein CSTF2 regulates BAD to inhibit apoptosis in glioblastoma. In International journal of biological macromolecules, 226, 915-926. doi:10.1016/j.ijbiomac.2022.12.044. https://pubmed.ncbi.nlm.nih.gov/36521710/