| Description |
Emerging evidence indicates that metabolic enzymes perform moonlighting functions, including modulating chemoresistance, during tumor progression. However, the underlying mechanisms remain to be elucidated. In this study, utilizing a genome-scale metabolic clustered regularly interspaced short palindromic repeats (CRISPR)-Cas9 knockout library screen, we find that loss of Glutamate-cysteine ligase modifier subunit (GCLM), a rate-limiting enzyme in glutathione biosynthesis, noticeably increases the sensitivity of colorectal cancer (CRC) cells to platinum-based chemotherapy. Mechanistically, we reveal a noncanonical mechanism through which nuclear GCLM competitively interacts with NF-kappa-B-repressing factor (NKRF), known as an NF-κB signaling inhibitor, to promote NF-κB activity and subsequently facilitate chemoresistance. In response to platinum drug treatment, P38 phosphorylates GCLM at T17, resulting in its recognition by importin a5 and subsequent nuclear translocation. Furthermore, high expression of nuclear GCLM is found in CRC tissues and is associated with poor prognosis and P38 activity. Overall, our findings highlight the essential nonmetabolic function and posttranslational regulatory mechanism of GCLM in promoting NF-κB activity and subsequent chemoresistance. |
