Division of General Surgery, Peking University First Hospital, Beijing, China.
Central laboratory, Peking University First Hospital, Beijing, China.
Neoplasia. 2021 May;23(5):461-472. doi: 10.1016/j.neo.2021.03.009. Epub 2021 Apr 18.
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 HS partially reversed the loss of chemoresistance phenotype after inhibiting xCT. Mechanistically, CTH derived HS 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 HS increased the stability of xCT through persulfidation of OTU domain-containing ubiquitin aldehyde-binding protein 1 at cysteine 91.
xCT 和转硫途径的增加与结直肠癌的代谢重编程有关。然而，这两个事件之间的相关性及其潜在的分子机制仍然不清楚。我们在结直肠癌的组织微阵列中测定了 xCT 的表达。采用 RNA 测序和体外功能测定来描绘转硫途径在维持 xCT 正常功能以保持化疗耐药表型中的作用。我们在体外和体内研究了阻断 xCT 和转硫途径的合成致死性。在结肠癌细胞中抑制 xCT 后，转硫途径的上调是明显的，外源性 HS 部分逆转了抑制 xCT 后化学耐药表型的丧失。在机制上，CTH 衍生的 HS 通过 OTU 结构域包含的泛素醛结合蛋白 1 上半胱氨酸 91 的过硫化作用增加了 xCT 的稳定性。AOAA 和 Erastin 在体外和体内都导致了合成致死性，这是通过增加铁死亡和细胞凋亡介导的。我们的研究结果表明，xCT 和转硫途径之间存在相互调节关系，这是一个可靶向的代谢脆弱性。在机制上，CTH 衍生的 HS 通过 OTU 结构域包含的泛素醛结合蛋白 1 上半胱氨酸 91 的过硫化作用增加了 xCT 的稳定性。
