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

Author

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  • Jin-Fei Lin

    (Sun Yat-sen University Cancer Center
    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
    The University of Hong Kong-Shenzhen Hospital)

  • Rui-Hua Xu

    (Sun Yat-sen University Cancer Center
    Chinese Academy of Medical Sciences)

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.

Suggested Citation

  • 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-Qi, 2025. "Nucleus-translocated GCLM promotes chemoresistance in colorectal cancer through a moonlighting function," Nature Communications, Nature, vol. 16(1), pages 1-18, December.
  • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-024-55568-1
    DOI: 10.1038/s41467-024-55568-1
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