CYLD, short for CYLD lysine 63 deubiquitinase, is a ubiquitin hydrolase. It plays crucial roles in immunity and cancer by regulating cellular pathways such as NF-κB, Wnt, and TGF-β pathways [1]. CYLD's function is significant in processes like inflammation, cell death, cell cycle progression, and cell transformation [1]. Research on diverse model systems, including gene knockout models, has been key to understanding CYLD's functions.

In prostate cancer, CYLD acts as a tumor suppressor gene. It is downregulated in PCa tissues, and its reduced expression is linked to higher pathological grades and clinical stages. CYLD inhibits tumor cell proliferation and promotes cell ferroptosis through the Hippo/YAP signaling pathway [2]. In melanoma, the tumor suppressor CYLD, as a deubiquitinase, along with the ubiquitin ligase TRIM15, regulates ERK activation via lysine-63-linked polyubiquitination. High TRIM15 and low CYLD expression are associated with poor prognosis [3]. In human papillomavirus-associated head and neck cancers, loss-of-function CYLD alterations lead to aberrant activation of growth-promoting signaling pathways, promoting tumorigenesis and malignant transformation [4]. In glioblastoma stem cells, FOSL1 promotes UBC9-dependent CYLD SUMOylation, inducing NF-κB activation and proneural-to-mesenchymal transition [5]. In nasopharyngeal carcinoma, CYLD binds to class I histone deacetylases, regulating cellular antioxidant response, DNA damage and repair, and radiosensitivity [6].

In conclusion, CYLD is a multifunctional deubiquitinase that plays essential roles in various biological processes and diseases. Studies using gene knockout or related models have revealed its significance in cancer-related processes such as tumorigenesis, cell proliferation, and metastasis, as well as in regulating signaling pathways and cellular responses to stress and radiation.

References:

1. Marín-Rubio, José L, Raote, Ishier, Inns, Joseph, Dobson-Stone, Carol, Rajan, Neil. 2023. CYLD in health and disease. In Disease models & mechanisms, 16, . doi:10.1242/dmm.050093. https://pubmed.ncbi.nlm.nih.gov/37387450/

2. Gu, Yanan, Wu, Shiqi, Fan, Junjie, Wang, Xinyang, Wu, Kaijie. 2024. CYLD regulates cell ferroptosis through Hippo/YAP signaling in prostate cancer progression. In Cell death & disease, 15, 79. doi:10.1038/s41419-024-06464-5. https://pubmed.ncbi.nlm.nih.gov/38246916/

3. Zhu, Guixin, Herlyn, Meenhard, Yang, Xiaolu. 2021. TRIM15 and CYLD regulate ERK activation via lysine-63-linked polyubiquitination. In Nature cell biology, 23, 978-991. doi:10.1038/s41556-021-00732-8. https://pubmed.ncbi.nlm.nih.gov/34497368/

4. Cui, Zhibin, Kang, Hyunseok, Grandis, Jennifer R, Johnson, Daniel E. 2020. CYLD Alterations in the Tumorigenesis and Progression of Human Papillomavirus-Associated Head and Neck Cancers. In Molecular cancer research : MCR, 19, 14-24. doi:10.1158/1541-7786.MCR-20-0565. https://pubmed.ncbi.nlm.nih.gov/32883697/

5. Chen, Zhengxin, Wang, Shuai, Li, Hai-Lin, Wu, Wei, Wang, Huibo. 2022. FOSL1 promotes proneural-to-mesenchymal transition of glioblastoma stem cells via UBC9/CYLD/NF-κB axis. In Molecular therapy : the journal of the American Society of Gene Therapy, 30, 2568-2583. doi:10.1016/j.ymthe.2021.10.028. https://pubmed.ncbi.nlm.nih.gov/35351656/

6. Li, Yueshuo, Yang, Chenxing, Xie, Longlong, Li, Xuejun, Cao, Ya. 2024. CYLD induces high oxidative stress and DNA damage through class I HDACs to promote radiosensitivity in nasopharyngeal carcinoma. In Cell death & disease, 15, 95. doi:10.1038/s41419-024-06419-w. https://pubmed.ncbi.nlm.nih.gov/38287022/