Fbxw10-KO Mouse

Fbxw10, also known as F-box and WD repeat domain containing 10, is an F-box protein of the E3 ubiquitin ligases. It is involved in the ubiquitination process, targeting specific proteins for degradation or modification, which plays a crucial role in regulating various cellular events and signaling pathways [1,2,3,4,5,6,7,8].

In hepatocellular carcinoma (HCC), male FBXW10-Tg(+) mice were more susceptible to tumorigenesis, changes in regenerative capacity, and liver injury and inflammation compared to FBXW10-Tg(-) mice. FBXW10 promoted HCC development in male mice and patients. Mechanistically, in male HCC, FBXW10 promotes K63-linked ANXA2 polyubiquitination and activation, which is required for S6K1-mediated phosphorylation. Activated ANXA2 translocates to the cell membrane, binds KRAS, and activates the MEK/ERK pathway, leading to HCC proliferation and lung metastasis. Also, FBXW10 promotes GAPDH polyubiquitination and activation through VRK2-dependent phosphorylation of GAPDH Ser151 residue, activating the NF-κB pathways and promoting HCC tumorigenesis and metastasis [1,2,4]. In colorectal cancer, knockout of FBXW10 in in vivo studies inhibited tumor proliferation and reduced liver metastasis as FBXW10 could ubiquitinate and degrade LATS2, affecting angiogenesis and liver metastasis [5].

In conclusion, Fbxw10 plays a significant role in the development of certain cancers, especially in male-biased HCC. The use of gene-modified mouse models, such as FBXW10-Tg(+) and FBXW10 knockout mice, has been crucial in uncovering its function in promoting tumorigenesis, metastasis, and associated signaling pathways in these disease conditions [1,2,4,5].

References:

1. Liu, Ze-Yu, Lin, Xiao-Tong, Zhang, Yu-Jun, Zhang, Lei-Da, Xie, Chuan-Ming. 2023. FBXW10-S6K1 promotes ANXA2 polyubiquitination and KRAS activation to drive hepatocellular carcinoma development in males. In Cancer letters, 566, 216257. doi:10.1016/j.canlet.2023.216257. https://pubmed.ncbi.nlm.nih.gov/37277019/

2. Lin, Xiao-Tong, Zhang, Jie, Liu, Ze-Yu, Yu, Hong-Qiang, Xie, Chuan-Ming. 2023. Elevated FBXW10 drives hepatocellular carcinoma tumorigenesis via AR-VRK2 phosphorylation-dependent GAPDH ubiquitination in male transgenic mice. In Cell reports, 42, 112812. doi:10.1016/j.celrep.2023.112812. https://pubmed.ncbi.nlm.nih.gov/37450367/

3. Sahay, Osheen, Barik, Ganesh Kumar, Islam, Sehbanul. 2023. FBXW10: a male-biased E3 ligase in liver cancer. In Trends in cancer, 9, 876-878. doi:10.1016/j.trecan.2023.09.004. https://pubmed.ncbi.nlm.nih.gov/37775405/

4. Luo, Yuan-Deng, Zhang, Jie, Fang, Lei, Bie, Ping, Xie, Chuan-Ming. . FBXW10 promotes hepatocarcinogenesis in male patients and mice. In Carcinogenesis, 41, 689-698. doi:10.1093/carcin/bgz138. https://pubmed.ncbi.nlm.nih.gov/31400758/

5. Zhang, Zheng-Yun, Sun, Jian-Hua, Liang, Ming-Jun, Guan, Jiao, Zhou, Zun-Qiang. 2023. The E3 ubiquitin ligase SCF (FBXW10)-mediated LATS2 degradation regulates angiogenesis and liver metastasis in colorectal cancer. In The international journal of biochemistry & cell biology, 158, 106408. doi:10.1016/j.biocel.2023.106408. https://pubmed.ncbi.nlm.nih.gov/36990424/

6. Feng, Zhou, Hui, Yan, Ling, Li, Peng, Wang, Lianwen, Zhang. 2013. FBXW10 is negatively regulated in transcription and expression level by protein O-GlcNAcylation. In Biochemical and biophysical research communications, 438, 427-32. doi:10.1016/j.bbrc.2013.07.091. https://pubmed.ncbi.nlm.nih.gov/23899520/

7. Luo, Wen, Xiao, Qiyu, Fu, Ying. 2025. ZNF169 promotes thyroid cancer progression via upregulating FBXW10. In Cell division, 20, 3. doi:10.1186/s13008-024-00139-5. https://pubmed.ncbi.nlm.nih.gov/39875985/

8. Chaturvedi, Pankaj, Parnaik, Veena K. 2010. Lamin A rod domain mutants target heterochromatin protein 1alpha and beta for proteasomal degradation by activation of F-box protein, FBXW10. In PloS one, 5, e10620. doi:10.1371/journal.pone.0010620. https://pubmed.ncbi.nlm.nih.gov/20498703/