Nucleus-translocated GCLM promotes chemoresistance in colorectal cancer through a moonlighting function
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 k...
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2025-01-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-024-55568-1 |
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| author | 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 Rui-Hua Xu |
| author_facet | 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 Rui-Hua Xu |
| author_sort | Jin-Fei Lin |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-470559a30b7448879bdbcb6b6b551f67 |
| institution | Kabale University |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-470559a30b7448879bdbcb6b6b551f672025-01-05T12:37:05ZengNature PortfolioNature Communications2041-17232025-01-0116111810.1038/s41467-024-55568-1Nucleus-translocated GCLM promotes chemoresistance in colorectal cancer through a moonlighting functionJin-Fei Lin0Ze-Xian Liu1Dong-Liang Chen2Ren-Ze Huang3Fen Cao4Kai Yu5Ting Li6Hai-Yu Mo7Hui Sheng8Zhi-Bing Liang9Kun Liao10Yi Han11Shan-Shan Li12Zhao-Lei Zeng13Song Gao14Huai-Qiang Ju15Rui-Hua Xu16Department of Medical Oncology, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer CenterDepartment of Medical Oncology, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer CenterDepartment of Medical Oncology, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer CenterDepartment of Medical Oncology, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer CenterDepartment of Biochemistry, Zhongshan School of Medicine, Sun Yat-sen UniversityDepartment of Genomic Medicine, The University of Texas MD Anderson Cancer CenterDepartment of Gastroenterology and Urology, Hunan Cancer Hospital/The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South UniversityDepartment of Medical Oncology, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer CenterDepartment of Medical Oncology, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer CenterDepartment of Clinical Oncology, Shenzhen Key Laboratory for Cancer Metastasis and Personalized Therapy, The University of Hong Kong-Shenzhen HospitalDepartment of Medical Oncology, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer CenterDepartment of Medical Oncology, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer CenterDepartment of Clinical Oncology, Shenzhen Key Laboratory for Cancer Metastasis and Personalized Therapy, The University of Hong Kong-Shenzhen HospitalDepartment of Medical Oncology, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer CenterDepartment of Medical Oncology, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer CenterDepartment of Medical Oncology, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer CenterDepartment of Medical Oncology, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer CenterAbstract 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.https://doi.org/10.1038/s41467-024-55568-1 |
| spellingShingle | 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 Rui-Hua Xu Nucleus-translocated GCLM promotes chemoresistance in colorectal cancer through a moonlighting function Nature Communications |
| title | Nucleus-translocated GCLM promotes chemoresistance in colorectal cancer through a moonlighting function |
| title_full | Nucleus-translocated GCLM promotes chemoresistance in colorectal cancer through a moonlighting function |
| title_fullStr | Nucleus-translocated GCLM promotes chemoresistance in colorectal cancer through a moonlighting function |
| title_full_unstemmed | Nucleus-translocated GCLM promotes chemoresistance in colorectal cancer through a moonlighting function |
| title_short | Nucleus-translocated GCLM promotes chemoresistance in colorectal cancer through a moonlighting function |
| title_sort | nucleus translocated gclm promotes chemoresistance in colorectal cancer through a moonlighting function |
| url | https://doi.org/10.1038/s41467-024-55568-1 |
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