Endogenous hydrogen sulfide regulates xCT stability through persulfidation of OTUB1 at cysteine 91 in colon cancer cells

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 H 2 S partially reversed the loss of chemoresistance phenotype after inhibiting xCT. Mechanistically, CTH derived H 2 S 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 H 2 S increased the stability of xCT through persulfidation of OTU domain-containing ubiquitin aldehyde-binding protein 1 at cysteine 91.

Hydrogen Sulfide Biology and Its Role in Cancer

“…H 2 S has an antioxidative effect by increasing GSH content and reducing ROS [ 215 ]. In addition, to reduce ferroptosis, GPX4 activity is inhibited while the Xc system is kept stable [ 216 , 217 ]. GSH depletion is an essential feature of ferroptosis.…”

“…The beneficial effects of H 2 S on ferroptosis suppression have recently been demonstrated in research. H 2 S inhibits ferroptosis by suppressing ALOX12 acetylation and controlling the stability of the xCT (the functional submit of the Xc system), according to Wang and Chen et al [ 216 , 222 ]. Therapy with the H 2 S donor GYY4137 reduces ferroptosis, which helps to reduce acute lung damage [ 223 ].…”

Targeting Ferroptosis by Ubiquitin System Enzymes: A Potential Therapeutic Strategy in Cancer

“…Rather than depending on its deubiquitination ability, OTUB1 stabilizes SLC7A11 by inhibiting the E2-conjugating enzymes recruited by E3 ligases 140 . Accumulating evidence has shown that depletion of OTUB1 sensitizes multiple tumor cells to ferrotopsis, including glioma 141 , colon cancer 142 , breast cancer 143 , and pancreatic cancer 144 , thereby modulating OTUB1 might be a promising strategy for cancer therapy. Palladium pyrithione complex (PdPT) is a pan-inhibitor of multiple DUBs, including USP7, USP10, USP14, USP15, USP25, and UCHL5, which contributes to ferroptosis and apoptosis in NSCLC cell lines.…”

Non-Canonical Programmed Cell Death in Colon Cancer

“…Mutual regulation between xCT and H2S can be suppressed by AOAA and Erastin. This combined therapy leads to ferroptosis in chemoresistance colon cancer cells [ 73 ]. It is well known that many saponins are anti-tumor drugs.…”