Chfr, short for Checkpoint with Forkhead-associated and Ring finger domains, is a gene involved in regulating entry into mitosis. It acts as a G2 phase/mitosis checkpoint, controlling chromosomal instability, and its inactivation can lead to tumorigenesis [1,7]. It is also an E3 ubiquitin ligase and has been associated with multiple biological pathways, such as those related to cell adhesion through its role in ubiquitylation-dependent degradation of VE-cadherin [2].

In gastric cancer, Chfr promoter hypermethylation is significantly higher in tumor tissues compared to normal tissues, and it may play a protective role, potentially serving as a biomarker for diagnosis and prognosis [1]. In endothelial cells, Chfr-knockout (ChfrΔEC) mice showed augmented VE-cadherin expression, and abrogation of LPS-induced VE-cadherin degradation, indicating its role in regulating endothelial junctional barrier in inflammation [2]. In ovarian cancer, CHFR expression was associated with serous histology, higher grade and stage, but no significant association was found between CHFR staining and survival or paclitaxel sensitivity [3]. In pancreatic ductal adenocarcinoma, higher CHFR expression and specific promoter methylation patterns were associated with longer survival, establishing them as independent prognostic factors [4]. In triple-negative breast cancer, CHFR destabilizes ZEB1, a driver of chemoresistance, and a HDAC inhibitor can increase CHFR expression to sensitize resistant cells to chemotherapy [5]. In breast cancer, CHFR promotes metastasis by mediating epithelial-to-mesenchymal transition [6]. In gastric carcinoma, CHFR promotes metastasis by activating AKT and ERK via the NRF2-ROS axis [8]. In advanced colorectal cancer, the extent of Chfr-promoter methylation can predict sensitivity to irinotecan-based systemic chemotherapy [9]. In vascular smooth muscle cells, circ_CHFR promotes PDGF-BB-induced proliferation, invasion, and migration through the miR-149-5p/NRP2 axis [10].

In conclusion, Chfr plays diverse and crucial roles in various biological processes and diseases. Its function in regulating mitosis, cell adhesion, and involvement in multiple signaling pathways are well-documented. Studies using gene knockout or conditional knockout mouse models, like ChfrΔEC mice, have been instrumental in revealing its role in specific biological processes such as endothelial barrier regulation during inflammation. In the context of diseases, especially cancers, Chfr's role in prognosis, chemoresistance, and metastasis highlights its potential as a biomarker and therapeutic target.

References:

1. Dai, Dongjun, Zhou, Bingluo, Xu, Wenxia, Jin, Hongchuan, Wang, Xian. 2019. CHFR Promoter Hypermethylation Is Associated with Gastric Cancer and Plays a Protective Role in Gastric Cancer Process. In Journal of Cancer, 10, 949-956. doi:10.7150/jca.27224. https://pubmed.ncbi.nlm.nih.gov/30854101/

2. Tiruppathi, Chinnaswamy, Wang, Dong-Mei, Ansari, Mohammad Owais, Niessen, Hans W M, Malik, Asrar B. 2023. Ubiquitin ligase CHFR mediated degradation of VE-cadherin through ubiquitylation disrupts endothelial adherens junctions. In Nature communications, 14, 6582. doi:10.1038/s41467-023-42225-2. https://pubmed.ncbi.nlm.nih.gov/37852964/

3. Wahner Hendrickson, Andrea E, Visscher, Daniel W, Hou, Xiaonan, Weroha, S John, Kaufmann, Scott H. 2021. CHFR and Paclitaxel Sensitivity of Ovarian Cancer. In Cancers, 13, . doi:10.3390/cancers13236043. https://pubmed.ncbi.nlm.nih.gov/34885153/

4. González-Borja, Iranzu, Alors-Pérez, Emilia, Amat, Irene, Castaño, Justo P, Viúdez, Antonio. 2021. Deciphering CHFR Role in Pancreatic Ductal Adenocarcinoma. In Frontiers in medicine, 8, 720128. doi:10.3389/fmed.2021.720128. https://pubmed.ncbi.nlm.nih.gov/34869418/

5. Luo, Hong, Zhou, Zhicheng, Huang, Shan, Kim, Jongchan, Zhang, Peijing. 2021. CHFR regulates chemoresistance in triple-negative breast cancer through destabilizing ZEB1. In Cell death & disease, 12, 820. doi:10.1038/s41419-021-04114-8. https://pubmed.ncbi.nlm.nih.gov/34462429/

6. Jiang, Guobin, Fang, Hongyan, Shang, Xi, Chen, Xiaopin, Cao, Feilin. 2021. CHFR‑mediated epithelial‑to‑mesenchymal transition promotes metastasis in human breast cancer cells. In Molecular medicine reports, 23, . doi:10.3892/mmr.2021.12090. https://pubmed.ncbi.nlm.nih.gov/33880594/

7. Sanbhnani, Sheru, Yeong, Foong May. 2011. CHFR: a key checkpoint component implicated in a wide range of cancers. In Cellular and molecular life sciences : CMLS, 69, 1669-87. doi:10.1007/s00018-011-0892-2. https://pubmed.ncbi.nlm.nih.gov/22159584/

8. He, Feiyun, Ye, Bin, Wu, Xiaomeng, Wang, Jianbo, Wang, Xiaojing. 2023. CHFR promotes metastasis of human gastric carcinoma by activating AKT and ERK via NRF2- ROS axis. In BMC gastroenterology, 23, 114. doi:10.1186/s12876-023-02724-4. https://pubmed.ncbi.nlm.nih.gov/37024798/

9. Hagiwara, Toshiaki, Sugimoto, Kiichi, Momose, Hirotaka, Brock, Malcolm V, Sakamoto, Kazuhiro. . CHFR-Promoter-Methylation Status Is Predictive of Response to Irinotecan-based Systemic Chemotherapy in Advanced Colorectal Cancer. In Anticancer research, 42, 697-707. doi:10.21873/anticanres.15528. https://pubmed.ncbi.nlm.nih.gov/35093868/

10. Wang, Meixue, Li, Chengliang, Cai, Tianzhi, Cao, Jinlong, Xin, Hong. . Circ_CHFR Promotes Platelet-Derived Growth Factor-BB-Induced Proliferation, Invasion, and Migration in Vascular Smooth Muscle Cells via the miR-149-5p/NRP2 Axis. In Journal of cardiovascular pharmacology, 79, e94-e102. doi:10.1097/FJC.0000000000001055. https://pubmed.ncbi.nlm.nih.gov/33990513/