USP11-mediated LSH deubiquitination inhibits ferroptosis in colorectal cancer through epigenetic activation of CYP24A1.

Autor: Duan J; Department of Cell Biology, School of Basic Medical Sciences, Peking University Health Science Center, 100191, Beijing, China., Huang D; Advanced Innovation Center for Human Brain Protection, and National Clinical Research Center for Geriatric Disorders, Xuanwu Hospital Capital Medical University, 100053, Beijing, China., Liu C; Program for Cancer and Cell Biology, Department of Human Anatomy, Histology and Embryology, School of Basic Medical Sciences, Peking University International Cancer Institute, 100191, Beijing, China., Lv Y; Colorectal Department of Quzhou Affiliated Hospital of Wenzhou Medical University, Quzhou People's Hospital, 324000, Quzhou, China., Zhang L; Program for Cancer and Cell Biology, Department of Human Anatomy, Histology and Embryology, School of Basic Medical Sciences, Peking University International Cancer Institute, 100191, Beijing, China., Chang F; Department of Otorhinolaryngology, Qilu Hospital of Shandong University, NHC Key Laboratory of Otorhinolaryngology (Shandong University), 250012, Jinan, China., Zeng X; Department of Cell Biology, School of Basic Medical Sciences, Peking University Health Science Center, 100191, Beijing, China., Li L; Department of Cell Biology, School of Basic Medical Sciences, Peking University Health Science Center, 100191, Beijing, China., Wang W; Department of Biochemistry and Molecular Biology, Peking University Health Science Center, 100191, Beijing, China. wwp@bjmu.edu.cn., Shao G; Department of Cell Biology, School of Basic Medical Sciences, Peking University Health Science Center, 100191, Beijing, China. gzshao@bjmu.edu.cn.
Jazyk: angličtina
Zdroj: Cell death & disease [Cell Death Dis] 2023 Jul 06; Vol. 14 (7), pp. 402. Date of Electronic Publication: 2023 Jul 06.
DOI: 10.1038/s41419-023-05915-9
Abstrakt: Ferroptosis is an iron-dependent form of regulated cell death characterized by lipid peroxidation. Colorectal cancer (CRC) cells evade ferroptosis despite their requirement of substantial iron and reactive oxygen species (ROS) to sustain active metabolism and extensive proliferation. However, the underlying mechanism is unclear. Herein, we report the role of lymphoid-specific helicase (LSH), a chromatin-remodeling protein, in suppressing erastin-induced ferroptosis in CRC cells. We demonstrate that erastin treatment leads to dose- and time-dependent downregulation of LSH in CRC cells, and depletion of LSH increases cell sensitivity to ferroptosis. Mechanistically, LSH interacts with and is stabilized by ubiquitin-specific protease 11 (USP11) via deubiquitination; this interaction was disrupted by erastin treatment, resulting in increased ubiquitination and LSH degradation. Moreover, we identified cytochrome P450 family 24 subfamily A member 1 (CYP24A1) as a transcriptional target of LSH. LSH binds to the CYP24A1 promoter, promoting nucleosome eviction and reducing H3K27me3 occupancy, thus leading to transcription of CYP24A1. This cascade inhibits excessive intracellular Ca 2+ influx, thereby reducing lipid peroxidation and ultimately conferring resistance to ferroptosis. Importantly, aberrant expression of USP11, LSH, and CYP24A1 is observed in CRC tissues and correlates with poor patient prognosis. Taken together, our study demonstrates the crucial role of the USP11/LSH/CYP24A1 signaling axis in inhibiting ferroptosis in CRC, highlighting its potential as a therapeutic target in CRC treatment.
(© 2023. The Author(s).)
Databáze: MEDLINE
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