xCT (Slc7a11) Regulation: Lessons from Cancer Research

The cystine/glutamate antiporter, also known as system X_c^-, has two roles: (1) imports cystine used to form glutathione (GSH), (2) regulates the extracellular concentration of glutamate. These roles are essential for brain function, as GSH is the most important antioxidant in the brain, and glutamate is the main excitatory neurotransmitter. This antiporter is composed of two subunits: xCT (encoded by the gene Slc7a11) and a heavy chain, CD98 (encoded by the gene Slc3a2). xCT is the subunit responsible for cystine/glutamate transport, while CD98 is responsible for the translocation of system X_c^- to the membrane. The antioxidant function of xCT has been highlighted by the discovery of ferroptosis, a distinctive form of programmed cell death triggered by lipid peroxidation and the accumulation of reactive oxygen species. In addition, numerous types of cancers have been shown to overexpress xCT to evade ferroptosis. The mechanisms by which healthy cells regulate xCT expression, the mechanisms responsible for xCT overexpression in cancer cells, and whether different types of cancers employ identical mechanisms to upregulate xCT have not been systematically studied. To answer these questions, we conducted a systematic review to consolidate the regulatory mechanisms governing xCT expression. We found that xCT expression is regulated at nearly all known levels, including epigenetic, transcriptional, post-transcriptional, translational, post-translational, and by protein-protein interactions, with some cell-type- and context-specific mechanisms. Overall, our work highlights the role of xCT and the breadth of axes through which its expression can be modulated.