Nucleus-translocated GCLM promotes chemoresistance in colorectal cancer through a moonlighting function

Jin-Fei Lin, Ze-Xian Liu, Dong-Liang Chen, Ren-Ze Huang, Fen Cao, Kai Yu, Ting Li, Hai-Yu Mo, Hui Sheng, Zhi-Bing Liang, Kun Liao, Yi Han, Shan-Shan Li, Zhao-Lei Zeng, Song Gao, Huai-Qiang Ju () and Rui-Hua Xu ()
Additional contact information
Jin-Fei Lin: Sun Yat-sen University Cancer Center
Ze-Xian Liu: Sun Yat-sen University Cancer Center
Dong-Liang Chen: Sun Yat-sen University Cancer Center
Ren-Ze Huang: Sun Yat-sen University Cancer Center
Fen Cao: Sun Yat-sen University
Kai Yu: The University of Texas MD Anderson Cancer Center
Ting Li: Central South University
Hai-Yu Mo: Sun Yat-sen University Cancer Center
Hui Sheng: Sun Yat-sen University Cancer Center
Zhi-Bing Liang: The University of Hong Kong-Shenzhen Hospital
Kun Liao: Sun Yat-sen University Cancer Center
Yi Han: Sun Yat-sen University Cancer Center
Shan-Shan Li: The University of Hong Kong-Shenzhen Hospital
Zhao-Lei Zeng: Sun Yat-sen University Cancer Center
Song Gao: Sun Yat-sen University Cancer Center
Huai-Qiang Ju: Sun Yat-sen University Cancer Center
Rui-Hua Xu: Sun Yat-sen University Cancer Center

Nature Communications, 2025, vol. 16, issue 1, 1-18

Abstract: Abstract Metabolic enzymes perform moonlighting functions during tumor progression, including the modulation of chemoresistance. However, the underlying mechanisms of these functions remain elusive. Here, utilizing a metabolic clustered regularly interspaced short palindromic repeats (CRISPR)-Cas9 knockout library screen, we observe that the 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 unveil a noncanonical mechanism through which nuclear GCLM competitively interacts with NF-kappa-B (NF-κB)-repressing factor (NKRF), to promote NF-κB activity and facilitate chemoresistance. In response to platinum drug treatment, GCLM is phosphorylated by P38 MAPK at T17, resulting in its recognition by importin a5 and subsequent nuclear translocation. Furthermore, elevated expression of nuclear GCLM and phospho-GCLM correlate with an unfavorable prognosis and poor benefit from standard chemotherapy. Overall, our work highlights the essential nonmetabolic role and posttranslational regulatory mechanism of GCLM in enhancing NF-κB activity and subsequent chemoresistance.

Date: 2025
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DOI: 10.1038/s41467-024-55568-1

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