Zic5, a member of the zinc finger protein of the cerebellum (ZIC) family, is crucial for animal growth and development. This transcription factor contains five Cys2His zinc finger domains and contributes to transcriptional regulation and chromatin remodeling. It is involved in multiple pathways, such as the Hedgehog (Hh) signaling pathway during retinal development [1].

In loss-of-function studies, Zic5 was found to be important for the differentiation of retinal pigmented epithelium (RPE) and the rod photoreceptor layer through suppressing Hh signaling. Zic5 interacts with Gli3, a critical Hh signaling molecule, disrupting Gli3/Gli3 homodimerization and stabilizing Gli3 protein [1]. In various cancer studies, Zic5 shows abnormal expression. For example, in hepatocellular carcinoma (HCC), cervical squamous cell carcinoma (CESC), prostate cancer, lung cancer, melanoma, nasopharyngeal carcinoma, and colon cancer, Zic5 overexpression promotes cell proliferation, migration, invasion, and cancer stemness, and is associated with poor prognosis [2,3,4,5,6,7,8,9].

In conclusion, Zic5 plays essential roles in both normal development, especially in retinal development through its interaction with the Hh signaling pathway, and in the progression of multiple cancers. Loss-of-function studies have been instrumental in revealing these functions, highlighting Zic5 as a potential therapeutic target in cancer treatment.

References:

1. Sun, Jian, Yoon, Jaeho, Lee, Moonsup, Hwang, Yoo-Seok, Daar, Ira O. . Zic5 stabilizes Gli3 via a non-transcriptional mechanism during retinal development. In Cell reports, 38, 110312. doi:10.1016/j.celrep.2022.110312. https://pubmed.ncbi.nlm.nih.gov/35108539/

2. Song, Wenping, Yu, Weijiang, Li, Ding, Chen, Jinhua, Zhang, Wenzhou. . ZIC5 promotes human hepatocellular carcinoma cell proliferation through upregulating COL1A1. In Journal of gastrointestinal oncology, 13, 1237-1247. doi:10.21037/jgo-22-335. https://pubmed.ncbi.nlm.nih.gov/35837163/

3. Jia, Qingge, Song, Junyang, Xu, Tianqi, Li, Mingyang, Yang, Xinyuan. 2022. ZIC5 promotes aggressiveness and cancer stemness in cervical squamous cell carcinoma. In Pathology, research and practice, 241, 154268. doi:10.1016/j.prp.2022.154268. https://pubmed.ncbi.nlm.nih.gov/36495760/

4. Tan, Yi-Fan, Zhang, Yang, Ge, Sheng-Yang, Sun, Chuan-Yu, Xia, Guo-Wei. 2022. AR-regulated ZIC5 contributes to the aggressiveness of prostate cancer. In Cell death discovery, 8, 393. doi:10.1038/s41420-022-01181-4. https://pubmed.ncbi.nlm.nih.gov/36127329/

5. Liu, Limin, Hu, Xingsheng, Sun, Dangze, Wu, Yao, Zhao, Zhanwei. 2018. ZIC5 facilitates the growth of hepatocellular carcinoma through activating Wnt/β-catenin pathway. In Biochemical and biophysical research communications, 503, 2173-2179. doi:10.1016/j.bbrc.2018.08.009. https://pubmed.ncbi.nlm.nih.gov/30086882/

6. Dong, Caijun, Li, Xiangguo, Li, Kang, Zheng, Chao, Ying, Jianjian. 2020. The Expression Pattern of ZIC5 and its Prognostic Value in Lung Cancer. In Cancer biotherapy & radiopharmaceuticals, 36, 407-411. doi:10.1089/cbr.2020.3775. https://pubmed.ncbi.nlm.nih.gov/32633542/

7. Satow, Reiko, Nakamura, Tomomi, Kato, Chiaki, Murayama, Yumi, Fukami, Kiyoko. 2016. ZIC5 Drives Melanoma Aggressiveness by PDGFD-Mediated Activation of FAK and STAT3. In Cancer research, 77, 366-377. doi:10.1158/0008-5472.CAN-16-0991. https://pubmed.ncbi.nlm.nih.gov/27671679/

8. Li, Tieqi, Zhang, Gehou, Li, Wei, Tan, Guolin, Ai, Jingang. 2023. MicroRNA-101-3p inhibits nasopharyngeal carcinoma cell proliferation and cisplatin resistance through ZIC5 down-regulation by targeting SOX2. In Biological chemistry, 404, 961-975. doi:10.1515/hsz-2022-0329. https://pubmed.ncbi.nlm.nih.gov/36752150/

9. Yang, Xiaoping, Wu, Pingfan, Wang, Zirui, Wu, Fanqi, Zhang, Dekui. 2022. Constructed the ceRNA network and predicted a FEZF1-AS1/miR-92b-3p/ZIC5 axis in colon cancer. In Molecular and cellular biochemistry, 478, 1083-1097. doi:10.1007/s11010-022-04578-y. https://pubmed.ncbi.nlm.nih.gov/36219353/