Usp35, a member of the deubiquitinases family, is associated with cell proliferation, mitosis, and plays a role in maintaining cellular homeostasis through protein de-ubiquitination [1,4,6]. It is involved in multiple cellular pathways, such as the PI3K/AKT signaling pathway, and has been implicated in various biological processes related to cancer development [3,6]. Genetic models, like gene knockout (KO) or conditional knockout (CKO) mouse models, are valuable for studying its functions.

In lung cancer, USP35 knockdown promoted ferroptosis, inhibited cell growth, colony formation, and tumor progression in cell lines and mouse tumor xenograft models. It directly interacted with ferroportin (FPN) and maintained its protein stability, modulating ferroptosis [1]. In ovarian cancer, silencing USP35 enhanced the activation of the STING-TBK1-IRF3 pathway, promoted type I interferon expression, and sensitized cells to cisplatin [2]. In HCC, USP35 knockdown decreased ABHD17C protein level, impaired the PI3K/AKT pathway, reduced proliferation, and mitigated migration and invasion, and xenograft assay showed that USP35 deficiency repressed HCC development in vivo [3]. In renal clear cell carcinoma, USP35 silencing led to reduced IAP proteins, increased apoptosis, and increased sensitivity to ferroptosis, and attenuated xenograft formation in nude mice [5].

In conclusion, through model-based research, USP35 has been shown to play crucial roles in multiple cancers, including lung, ovarian, liver, and renal clear cell carcinomas. KO/CKO mouse models have revealed its functions in promoting tumor cell survival by modulating processes like ferroptosis, apoptosis, and key signaling pathways, highlighting its potential as a therapeutic target in these cancer types.

References:

1. Tang, Zheng, Jiang, Wanli, Mao, Ming, Chen, Jiakuan, Cheng, Nitao. . Deubiquitinase USP35 modulates ferroptosis in lung cancer via targeting ferroportin. In Clinical and translational medicine, 11, e390. doi:10.1002/ctm2.390. https://pubmed.ncbi.nlm.nih.gov/33931967/

2. Zhang, Jiawen, Chen, Yunfei, Chen, Xianfei, Wang, Ping, Fang, Lan. 2020. Deubiquitinase USP35 restrains STING-mediated interferon signaling in ovarian cancer. In Cell death and differentiation, 28, 139-155. doi:10.1038/s41418-020-0588-y. https://pubmed.ncbi.nlm.nih.gov/32678307/

3. Wang, Linpei, Wang, Jiawei, Ma, Xiaoqiu, Wang, Wei, Wu, Jian. 2023. USP35 promotes HCC development by stabilizing ABHD17C and activating the PI3K/AKT signaling pathway. In Cell death discovery, 9, 421. doi:10.1038/s41420-023-01714-5. https://pubmed.ncbi.nlm.nih.gov/37993419/

4. Park, Jinyoung, Shin, Sang Chul, Jin, Kyeong Sik, Kim, Eunice EunKyeong, Song, Eun Joo. 2023. USP35 dimer prevents its degradation by E3 ligase CHIP through auto-deubiquitinating activity. In Cellular and molecular life sciences : CMLS, 80, 112. doi:10.1007/s00018-023-04740-9. https://pubmed.ncbi.nlm.nih.gov/37004621/

5. Wang, Shanshan, Wang, Taishu, Zhang, Xuehong, Liu, Quentin, Liu, Han. 2023. The deubiquitylating enzyme USP35 restricts regulated cell death to promote survival of renal clear cell carcinoma. In Cell death and differentiation, 30, 1757-1770. doi:10.1038/s41418-023-01176-3. https://pubmed.ncbi.nlm.nih.gov/37173391/

6. Lv, Tao, Zhang, Bo, Jiang, Chenghao, Yang, Jiayin, Zhou, Yongjie. 2023. USP35 promotes hepatocellular carcinoma progression by protecting PKM2 from ubiquitination‑mediated degradation. In International journal of oncology, 63, . doi:10.3892/ijo.2023.5561. https://pubmed.ncbi.nlm.nih.gov/37594129/