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

Abstract

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 Ca2+ 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.

Therapeutic strategies of targeting non-apoptotic regulated cell death (RCD) with small-molecule compounds in cancer

“…Moreover, p53 also functions in ferroptosis and lysosome-dependent cell death. It is noteworthy that members of the deubiquitinase family, such as USP8/11/18/48 and OTUD1/4, along with the heat shock protein family (HSP70/90/A8), exert precise regulatory effects on multiple RCD subroutines 313 , 314 , 457 , 458 , 459 , 460 .…”

Protein modification and degradation in ferroptosis

“…This destabilization is facilitated by the cullin-RING E3 ubiquitin ligase complex Cullin-RING ligase 4 (CRL4)-DDB1 and CUL4 associated factor 8 (DCAF8), which mediates polyubiquitination and subsequent proteasomal degradation of HELLS in cancer cells [ 158 ]. Furthermore, the deubiquitinating enzymes ubiquitin specific peptidase 5 (USP5) and USP11 inhibit ferroptosis by mediating the deubiquitination and stabilization of HELLS in hepatocellular carcinoma and colorectal cancer, respectively [ 159 , 160 ].…”

The role of ferroptosis in intervertebral disc degeneration

“…It has been reported that USP11 promotes autophagy activation and induces ferroptosis by deubiquitinating and stabilizing Beclin 1, thereby regulating spinal cord ischemia-reperfusion injury ( Rong et al, 2022 ). In addition, Duan et al found that USP11 can mediate LSH deubiquitination and activate CYP24A1 to inhibit ferroptosis in colorectal cancer ( Duan et al, 2023 ). Zhu et al found that Sirt3 decreased and ferroptosis occurred after the development of IVDD.…”