High-glucose-associated YTHDC1 lactylation reduces the sensitivity of bladder cancer to enfortumab vedotin therapy
Summary: Hyperglycemia is a recognized risk factor for bladder cancer (BC). Enfortumab vedotin (EV), the first NECTIN4-targeting antibody-drug conjugate, demonstrates promising clinical efficacy in patients with advanced BC. In this study, we show that EV treatment is less effective in BC patients w...
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| Format: | Article |
| Language: | English |
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Elsevier
2025-04-01
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| Series: | Cell Reports |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S221112472500316X |
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| author | Zhuo Xing Tiejun Yang Xurui Li Haozhe Xu Yulong Hong Shuai Shao Tao Li Liefu Ye Yuan Li Xin Jin Yongbao Wei |
| author_facet | Zhuo Xing Tiejun Yang Xurui Li Haozhe Xu Yulong Hong Shuai Shao Tao Li Liefu Ye Yuan Li Xin Jin Yongbao Wei |
| author_sort | Zhuo Xing |
| collection | DOAJ |
| description | Summary: Hyperglycemia is a recognized risk factor for bladder cancer (BC). Enfortumab vedotin (EV), the first NECTIN4-targeting antibody-drug conjugate, demonstrates promising clinical efficacy in patients with advanced BC. In this study, we show that EV treatment is less effective in BC patients with diabetes than in those with normoglycemia. The subsequent in vitro and in vivo experiments indicate that high glucose decreases the sensitivity of BC cells to EV. Mechanistically, lactate overproduction associated with high glucose promotes AARS1-mediated YTHDC1 lactylation and enhances RNF183-mediated YTHDC1 ubiquitination. Downregulated YTHDC1 reduces JUND mRNA stability in an m6A-dependent manner, subsequently decreasing NECTIN4 expression and EV responsiveness. Our study identifies a high-glucose-associated lactate-AARS1-YTHDC1-JUND-NECTIN4 axis that affects EV sensitivity in BC. Targeting this axis with JUND activators or β-alanine may offer therapeutic strategies to enhance the sensitivity of BC cells to EV. |
| format | Article |
| id | doaj-art-e2eb0a9dba744c63b31739b8570360fb |
| institution | OA Journals |
| issn | 2211-1247 |
| language | English |
| publishDate | 2025-04-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Cell Reports |
| spelling | doaj-art-e2eb0a9dba744c63b31739b8570360fb2025-08-20T02:09:33ZengElsevierCell Reports2211-12472025-04-0144411554510.1016/j.celrep.2025.115545High-glucose-associated YTHDC1 lactylation reduces the sensitivity of bladder cancer to enfortumab vedotin therapyZhuo Xing0Tiejun Yang1Xurui Li2Haozhe Xu3Yulong Hong4Shuai Shao5Tao Li6Liefu Ye7Yuan Li8Xin Jin9Yongbao Wei10Department of Urology, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, ChinaThe Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou 450008, ChinaThe Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou 450008, ChinaDepartment of Urology, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, ChinaDepartment of Urology, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, ChinaDepartment of Urology, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, ChinaShengli Clinical Medical College of Fujian Medical University, Department of Urology, Fujian Provincial Hospital, Fuzhou University Affiliated Provincial Hospital, No. 134, Dong Street, Fuzhou 350001, People's Republic of ChinaShengli Clinical Medical College of Fujian Medical University, Department of Urology, Fujian Provincial Hospital, Fuzhou University Affiliated Provincial Hospital, No. 134, Dong Street, Fuzhou 350001, People's Republic of ChinaDepartment of Urology, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, China; Corresponding authorDepartment of Urology, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, China; FuRong Laboratory, Changsha 410078, Hunan, China; Corresponding authorShengli Clinical Medical College of Fujian Medical University, Department of Urology, Fujian Provincial Hospital, Fuzhou University Affiliated Provincial Hospital, No. 134, Dong Street, Fuzhou 350001, People's Republic of China; Corresponding authorSummary: Hyperglycemia is a recognized risk factor for bladder cancer (BC). Enfortumab vedotin (EV), the first NECTIN4-targeting antibody-drug conjugate, demonstrates promising clinical efficacy in patients with advanced BC. In this study, we show that EV treatment is less effective in BC patients with diabetes than in those with normoglycemia. The subsequent in vitro and in vivo experiments indicate that high glucose decreases the sensitivity of BC cells to EV. Mechanistically, lactate overproduction associated with high glucose promotes AARS1-mediated YTHDC1 lactylation and enhances RNF183-mediated YTHDC1 ubiquitination. Downregulated YTHDC1 reduces JUND mRNA stability in an m6A-dependent manner, subsequently decreasing NECTIN4 expression and EV responsiveness. Our study identifies a high-glucose-associated lactate-AARS1-YTHDC1-JUND-NECTIN4 axis that affects EV sensitivity in BC. Targeting this axis with JUND activators or β-alanine may offer therapeutic strategies to enhance the sensitivity of BC cells to EV.http://www.sciencedirect.com/science/article/pii/S221112472500316XCP: Cancer |
| spellingShingle | Zhuo Xing Tiejun Yang Xurui Li Haozhe Xu Yulong Hong Shuai Shao Tao Li Liefu Ye Yuan Li Xin Jin Yongbao Wei High-glucose-associated YTHDC1 lactylation reduces the sensitivity of bladder cancer to enfortumab vedotin therapy Cell Reports CP: Cancer |
| title | High-glucose-associated YTHDC1 lactylation reduces the sensitivity of bladder cancer to enfortumab vedotin therapy |
| title_full | High-glucose-associated YTHDC1 lactylation reduces the sensitivity of bladder cancer to enfortumab vedotin therapy |
| title_fullStr | High-glucose-associated YTHDC1 lactylation reduces the sensitivity of bladder cancer to enfortumab vedotin therapy |
| title_full_unstemmed | High-glucose-associated YTHDC1 lactylation reduces the sensitivity of bladder cancer to enfortumab vedotin therapy |
| title_short | High-glucose-associated YTHDC1 lactylation reduces the sensitivity of bladder cancer to enfortumab vedotin therapy |
| title_sort | high glucose associated ythdc1 lactylation reduces the sensitivity of bladder cancer to enfortumab vedotin therapy |
| topic | CP: Cancer |
| url | http://www.sciencedirect.com/science/article/pii/S221112472500316X |
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