1. Endogenous hydrogen sulfide regulates xCT stability through persulfidation of OTUB1 at cysteine 91 in colon cancer cells
- Author
-
Dingfang Bu, Pengyuan Wang, Yisheng Pan, Xin Wang, Jing Zhu, Taohua Yue, Shanwen Chen, Yucun Liu, and Shihao Guo
- Subjects
0301 basic medicine ,Cancer Research ,Synthetic lethality ,Amino Acid Transport System y+ ,Gene Expression ,Transsulfuration pathway ,Models, Biological ,Mice ,03 medical and health sciences ,0302 clinical medicine ,Ubiquitin ,In vivo ,Cell Line, Tumor ,Animals ,Humans ,Ferroptosis ,Cysteine ,RC254-282 ,Original Research ,Deubiquitinating Enzymes ,biology ,Hydrogen sulfide ,Protein Stability ,Chemistry ,xCT ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,Immunohistochemistry ,In vitro ,Cell biology ,Gene Expression Regulation, Neoplastic ,Disease Models, Animal ,030104 developmental biology ,Tissue Array Analysis ,OTUB1 ,Apoptosis ,030220 oncology & carcinogenesis ,Colonic Neoplasms ,biology.protein ,Fluorouracil ,Synthetic Lethal Mutations ,Protein Processing, Post-Translational ,Protein Binding - Abstract
Increased xCT and transsulfuration pathway has been associated with metabolic reprogramming of colorectal cancer. However, the correlation between these 2 events and the underlying molecular mechanism remains obscure. xCT expression was determined in tissue microarrays of colorectal cancer. RNA sequencing and functional assays in vitro was adopted to delineate the involvement of transsulfuration pathway in the proper function of xCT in maintaining the chemoresistant phenotype. The synthetic lethality of blocking xCT and the transsulfuration pathway was investigated both in vitro and in vivo. The up-regulation of the transsulfuration pathway after inhibiting xCT in colon cancer cells was evident and exogenous H2S partially reversed the loss of chemoresistance phenotype after inhibiting xCT. Mechanistically, CTH derived H2S increased the stability of xCT through persulfidation of OTU domain-containing ubiquitin aldehyde-binding protein 1 at cysteine 91. AOAA and Erastin resulted in synthetic lethality both in vitro and in vivo, which was mediated through increased ferroptosis and apoptosis. Our findings suggest that a reciprocal regulation exists between xCT and the transsulfuration pathway, which is a targetable metabolic vulnerability. Mechanistically, CTH derived H2S increased the stability of xCT through persulfidation of OTU domain-containing ubiquitin aldehyde-binding protein 1 at cysteine 91.
- Published
- 2021