2. Academic Validation
  3. Nucleus-translocated GCLM promotes chemoresistance in colorectal cancer through a moonlighting function

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

  • Nat Commun. 2025 Jan 2;16(1):263. doi: 10.1038/s41467-024-55568-1.
Jin-Fei Lin # 1 2,  Ze-Xian Liu # 1,  Dong-Liang Chen # 1,  Ren-Ze Huang # 1,  Fen Cao 3,  Kai Yu 4,  Ting Li 5,  Hai-Yu Mo 1,  Hui Sheng 1,  Zhi-Bing Liang 6,  Kun Liao 1,  Yi Han 1,  Shan-Shan Li 6,  Zhao-Lei Zeng 1,  Song Gao 1,  Huai-Qiang Ju 7 8,  Rui-Hua Xu 9 10
Affiliations

Affiliations

  • 1 Department of Medical Oncology, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, PR China.
  • 2 Department of Clinical Laboratory, Sun Yat-Sen University Cancer Center, Guangzhou, PR China.
  • 3 Department of Biochemistry, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, PR China.
  • 4 Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
  • 5 Department of Gastroenterology and Urology, Hunan Cancer Hospital/The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, PR China.
  • 6 Department of Clinical Oncology, Shenzhen Key Laboratory for Cancer Metastasis and Personalized Therapy, The University of Hong Kong-Shenzhen Hospital, Shenzhen, PR China.
  • 7 Department of Medical Oncology, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, PR China. juhq@sysucc.org.cn.
  • 8 Department of Clinical Oncology, Shenzhen Key Laboratory for Cancer Metastasis and Personalized Therapy, The University of Hong Kong-Shenzhen Hospital, Shenzhen, PR China. juhq@sysucc.org.cn.
  • 9 Department of Medical Oncology, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, PR China. xurh@sysucc.org.cn.
  • 10 Research Unit of Precision Diagnosis and Treatment for Gastrointestinal Cancer, Chinese Academy of Medical Sciences, Guangzhou, PR China. xurh@sysucc.org.cn.
  • # Contributed equally.
PMID: 39747101 DOI: 10.1038/s41467-024-55568-1
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.

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