Ctbp2, also known as C-terminal binding protein 2, is a transcriptional coregulator that plays significant roles in multiple biological processes. It is involved in cellular development, apoptosis, and metastasis, and is associated with various signaling pathways such as Wnt/β -catenin, SHH -GLI1, and the regulation of mRNA methylation [1-6]. Its function in regulating gene expression makes it important for understanding normal development and disease pathogenesis, and genetic models like gene knockout (KO) mouse models are valuable for studying its functions.

In head and neck squamous cell carcinoma, CTBP2 acts as a cofactor of PCIF1 to catalyze m6Am deposition on mRNA, promoting tumor progression. Knocking out CTBP2 reduces PCIF1 occupancy on TET2 mRNA, a tumor suppressor, and negatively regulates TET2 mRNA translation [1]. In glioblastoma, CtBP2 interacts with ZBTB18 to promote malignancy. CtBP2 shRNA counteracts the effect of ZBTB18 shRNA on inhibiting cell apoptosis, and promotes cell proliferation, viability, EMT, invasion, and migration. It also blocks cells at the G0/G1 phase and suppresses the SHH -GLI1 pathway in mice [2]. In esophageal squamous cell cancer, CtBP2 interacts with TGIF and promotes the malignant progression of the cancer through the Wnt/β -catenin pathway [3]. In acute myeloid leukemia, the interaction of EVI1 with CTBP2 via a single PLDLS motif is indispensable for leukemic transformation, and a 4× PLDLS repeat construct can inhibit the proliferation of 3q26/MECOM rearranged AML in vitro and in xenotransplant models [4]. In obesity-related metabolic derangements, CtBP2 is diminished in pancreatic islets, and pancreatic β -cell-specific CtBP2-deficient mice show glucose intolerance with impaired insulin secretion, suggesting CtBP2 is crucial for maintaining β -cell integrity [5]. In prostate cancer, downregulation of CtBP2 in PC3 cells inhibits cell proliferation by inducing apoptosis and decreasing the level of c-Myc and its target HSPC111 [6].

In conclusion, Ctbp2 is a crucial transcriptional coregulator involved in multiple biological processes and disease conditions. Model-based research, especially KO mouse models, has revealed its significant roles in cancer development and progression, as well as in metabolic diseases related to obesity. Understanding Ctbp2 provides insights into disease mechanisms and potential therapeutic targets.

References:

1. Li, Kang, Chen, Jie, Zhang, Caihua, Chen, Qianming, Chen, Demeng. 2023. The CTBP2-PCIF1 complex regulates m6Am modification of mRNA in head and neck squamous cell carcinoma. In The Journal of clinical investigation, 133, . doi:10.1172/JCI170173. https://pubmed.ncbi.nlm.nih.gov/37643007/

2. Chen, Liang, Wang, Lu, Qin, Jun, Wei, De-Sheng. 2020. CtBP2 interacts with ZBTB18 to promote malignancy of glioblastoma. In Life sciences, 262, 118477. doi:10.1016/j.lfs.2020.118477. https://pubmed.ncbi.nlm.nih.gov/32971103/

3. Ju, Qianqian, Jiang, Maorong, Huang, Wenxin, Luo, Zhenghong, Shi, Hui. 2021. CtBP2 interacts with TGIF to promote the progression of esophageal squamous cell cancer through the Wnt/β‑catenin pathway. In Oncology reports, 47, . doi:10.3892/or.2021.8240. https://pubmed.ncbi.nlm.nih.gov/34878149/

4. Pastoors, Dorien, Havermans, Marije, Mulet-Lazaro, Roger, Bindels, Eric, Delwel, Ruud. 2024. Oncogene EVI1 drives acute myeloid leukemia via a targetable interaction with CTBP2. In Science advances, 10, eadk9076. doi:10.1126/sciadv.adk9076. https://pubmed.ncbi.nlm.nih.gov/38748792/

5. Sekiya, Motohiro, Ma, Yang, Kainoh, Kenta, Takahashi, Satoru, Shimano, Hitoshi. 2023. Loss of CtBP2 may be a mechanistic link between metabolic derangements and progressive impairment of pancreatic β cell function. In Cell reports, 42, 112914. doi:10.1016/j.celrep.2023.112914. https://pubmed.ncbi.nlm.nih.gov/37557182/

6. Zhang, Changwen, Gao, Chao, Xu, Yong, Zhang, Zhihong. 2014. CtBP2 could promote prostate cancer cell proliferation through c-Myc signaling. In Gene, 546, 73-9. doi:10.1016/j.gene.2014.05.032. https://pubmed.ncbi.nlm.nih.gov/24835310/