NSUN2 promotes colorectal cancer progression and increases lapatinib sensitivity by enhancing CUL4B/ErbB‐STAT3 signalling in a non‐m5C manner
Abstract NSUN2, a major methyltransferase that catalyzes m5C methylation in eukaryotes, is known to be implicated in the development of multiple cancers. However, its role in colorectal cancer (CRC) and the related molecular mechanisms have yet to be sufficiently determined. Here, we conducted an an...
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Wiley
2025-04-01
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| Series: | Clinical and Translational Medicine |
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| Online Access: | https://doi.org/10.1002/ctm2.70282 |
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| author | Yuanbo Hu Chenbin Chen Kezhi Lin Xinya Tong Tingting Huang Tianle Qiu Xietao Chen Jun Xu Wangkai Xie Xiangwei Sun Shiyu Feng Mingdong Lu Zhiguang Zhao Xiaodong Chen Xiangyang Xue Xian Shen |
| author_facet | Yuanbo Hu Chenbin Chen Kezhi Lin Xinya Tong Tingting Huang Tianle Qiu Xietao Chen Jun Xu Wangkai Xie Xiangwei Sun Shiyu Feng Mingdong Lu Zhiguang Zhao Xiaodong Chen Xiangyang Xue Xian Shen |
| author_sort | Yuanbo Hu |
| collection | DOAJ |
| description | Abstract NSUN2, a major methyltransferase that catalyzes m5C methylation in eukaryotes, is known to be implicated in the development of multiple cancers. However, its role in colorectal cancer (CRC) and the related molecular mechanisms have yet to be sufficiently determined. Here, we conducted an analysis of public database (722 CRC patients) and two distinct cohorts from our centre (1559 CRC patients), which revealed that NSUN2 is upregulated in CRC and correlates with unfavourable prognosis. Our analyses also showed that NSUN2 promotes the proliferation and metastasis capabilities of CRC cells. Intriguingly, NSUN2 was found to promote CRC via an m5C‐independent mechanism, which has not been previously reported. Overexpression of both wild‐type and m5C enzymatic‐dead mutant NSUN2 upregulated and activated the ErbB‐STAT3 signalling pathway. We also found that both wild‐type and the m5C enzymatic‐dead mutant NSUN2 closely interacted with CUL4B. Silencing of CUL4B effectively inhibited the m5C‐independent function of NSUN2. Moreover, overexpression of NSUN2 enhanced the sensitivity of CRC cells to lapatinib. Taken together, our findings revealed a novel m5C‐independent mechanism for NSUN2 in the malignancy and lapatinib sensitivity of CRC via activation of the CUL4B/ErbB‐STAT3 pathway, which provides a potential therapeutic strategy for patients with CRC. Highlights NSUN2 is upregulated in CRC and associated with poor prognosis of CRC patients. NSUN2 promotes CRC malignancy independently of its m5C‐enzymatic activity, a mechanism that has not been previously reported. The non‐m5C carcinogenic roles of NSUN2 may be mediated through interactions with CUL4B, thereby activating the ErbB‐STAT3 signalling pathway. NSUN2‐mediated upregulation of ErbB‐STAT3 pathway enhances the sensitivity of CRC to lapatinib treatment. |
| format | Article |
| id | doaj-art-44225dbf872543729f34becfe1f6829e |
| institution | DOAJ |
| issn | 2001-1326 |
| language | English |
| publishDate | 2025-04-01 |
| publisher | Wiley |
| record_format | Article |
| series | Clinical and Translational Medicine |
| spelling | doaj-art-44225dbf872543729f34becfe1f6829e2025-08-20T03:09:28ZengWileyClinical and Translational Medicine2001-13262025-04-01154n/an/a10.1002/ctm2.70282NSUN2 promotes colorectal cancer progression and increases lapatinib sensitivity by enhancing CUL4B/ErbB‐STAT3 signalling in a non‐m5C mannerYuanbo Hu0Chenbin Chen1Kezhi Lin2Xinya Tong3Tingting Huang4Tianle Qiu5Xietao Chen6Jun Xu7Wangkai Xie8Xiangwei Sun9Shiyu Feng10Mingdong Lu11Zhiguang Zhao12Xiaodong Chen13Xiangyang Xue14Xian Shen15Department of General Surgery The First Affiliated Hospital of Wenzhou Medical University Wenzhou ChinaDepartment of General Surgery The First Affiliated Hospital of Wenzhou Medical University Wenzhou ChinaExperiemtial Center of Basic Medicine, School of Basic Medical Sciences Wenzhou Medical University Wenzhou ChinaDepartment of Microbiology and Immunology, Institute of Molecular Virology and Immunology, School of Basic Medical Sciences Wenzhou Medical University Wenzhou ChinaDepartment of Microbiology and Immunology, Institute of Molecular Virology and Immunology, School of Basic Medical Sciences Wenzhou Medical University Wenzhou ChinaDepartment of Microbiology and Immunology, Institute of Molecular Virology and Immunology, School of Basic Medical Sciences Wenzhou Medical University Wenzhou ChinaDepartment of General Surgery The First Affiliated Hospital of Wenzhou Medical University Wenzhou ChinaDepartment of General Surgery The First Affiliated Hospital of Wenzhou Medical University Wenzhou ChinaZhejiang Key Laboratory of Intelligent Cancer Biomarker Discovery and Translation The First Affiliated Hospital of Wenzhou Medical University Wenzhou ChinaDepartment of General Surgery The First Affiliated Hospital of Wenzhou Medical University Wenzhou ChinaDepartment of Microbiology and Immunology, Institute of Molecular Virology and Immunology, School of Basic Medical Sciences Wenzhou Medical University Wenzhou ChinaDepartment of General Surgery The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University Wenzhou ChinaDepartment of Pathology The Second Affiliated Hospital & Yuying Children's Hospital of Wenzhou Medical University Wenzhou ChinaDepartment of General Surgery The First Affiliated Hospital of Wenzhou Medical University Wenzhou ChinaZhejiang Key Laboratory of Intelligent Cancer Biomarker Discovery and Translation The First Affiliated Hospital of Wenzhou Medical University Wenzhou ChinaDepartment of General Surgery The First Affiliated Hospital of Wenzhou Medical University Wenzhou ChinaAbstract NSUN2, a major methyltransferase that catalyzes m5C methylation in eukaryotes, is known to be implicated in the development of multiple cancers. However, its role in colorectal cancer (CRC) and the related molecular mechanisms have yet to be sufficiently determined. Here, we conducted an analysis of public database (722 CRC patients) and two distinct cohorts from our centre (1559 CRC patients), which revealed that NSUN2 is upregulated in CRC and correlates with unfavourable prognosis. Our analyses also showed that NSUN2 promotes the proliferation and metastasis capabilities of CRC cells. Intriguingly, NSUN2 was found to promote CRC via an m5C‐independent mechanism, which has not been previously reported. Overexpression of both wild‐type and m5C enzymatic‐dead mutant NSUN2 upregulated and activated the ErbB‐STAT3 signalling pathway. We also found that both wild‐type and the m5C enzymatic‐dead mutant NSUN2 closely interacted with CUL4B. Silencing of CUL4B effectively inhibited the m5C‐independent function of NSUN2. Moreover, overexpression of NSUN2 enhanced the sensitivity of CRC cells to lapatinib. Taken together, our findings revealed a novel m5C‐independent mechanism for NSUN2 in the malignancy and lapatinib sensitivity of CRC via activation of the CUL4B/ErbB‐STAT3 pathway, which provides a potential therapeutic strategy for patients with CRC. Highlights NSUN2 is upregulated in CRC and associated with poor prognosis of CRC patients. NSUN2 promotes CRC malignancy independently of its m5C‐enzymatic activity, a mechanism that has not been previously reported. The non‐m5C carcinogenic roles of NSUN2 may be mediated through interactions with CUL4B, thereby activating the ErbB‐STAT3 signalling pathway. NSUN2‐mediated upregulation of ErbB‐STAT3 pathway enhances the sensitivity of CRC to lapatinib treatment.https://doi.org/10.1002/ctm2.70282Colorectal cancerErbB‐STAT3 signalling pathwaym5C‐independent functionNSUN2 |
| spellingShingle | Yuanbo Hu Chenbin Chen Kezhi Lin Xinya Tong Tingting Huang Tianle Qiu Xietao Chen Jun Xu Wangkai Xie Xiangwei Sun Shiyu Feng Mingdong Lu Zhiguang Zhao Xiaodong Chen Xiangyang Xue Xian Shen NSUN2 promotes colorectal cancer progression and increases lapatinib sensitivity by enhancing CUL4B/ErbB‐STAT3 signalling in a non‐m5C manner Clinical and Translational Medicine Colorectal cancer ErbB‐STAT3 signalling pathway m5C‐independent function NSUN2 |
| title | NSUN2 promotes colorectal cancer progression and increases lapatinib sensitivity by enhancing CUL4B/ErbB‐STAT3 signalling in a non‐m5C manner |
| title_full | NSUN2 promotes colorectal cancer progression and increases lapatinib sensitivity by enhancing CUL4B/ErbB‐STAT3 signalling in a non‐m5C manner |
| title_fullStr | NSUN2 promotes colorectal cancer progression and increases lapatinib sensitivity by enhancing CUL4B/ErbB‐STAT3 signalling in a non‐m5C manner |
| title_full_unstemmed | NSUN2 promotes colorectal cancer progression and increases lapatinib sensitivity by enhancing CUL4B/ErbB‐STAT3 signalling in a non‐m5C manner |
| title_short | NSUN2 promotes colorectal cancer progression and increases lapatinib sensitivity by enhancing CUL4B/ErbB‐STAT3 signalling in a non‐m5C manner |
| title_sort | nsun2 promotes colorectal cancer progression and increases lapatinib sensitivity by enhancing cul4b erbb stat3 signalling in a non m5c manner |
| topic | Colorectal cancer ErbB‐STAT3 signalling pathway m5C‐independent function NSUN2 |
| url | https://doi.org/10.1002/ctm2.70282 |
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