TTC36 promotes proliferation and drug resistance in hepatocellular carcinoma cells by inhibiting c-Myc degradation
Abstract High c-Myc protein accumulation contributes to the proliferation, invasion, and drug resistance in multiple cancer cells, but the underlying mechanism about c-Myc accumulation remains not to be elucidated. Here, we demonstrate that TTC36 promotes c-Myc protein accumulation in hepatocellular...
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| Format: | Article |
| Language: | English |
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Nature Publishing Group
2025-04-01
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| Series: | Cell Death and Disease |
| Online Access: | https://doi.org/10.1038/s41419-025-07663-4 |
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| _version_ | 1850173075909246976 |
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| author | Fengling Shao Runzhi Wang Xinyi Li Yanxia Hu Zaikuan Zhang Jing Cai Jieru Yang Xiaosong Feng Suxia Ren Zengyi Huang Yajun Xie |
| author_facet | Fengling Shao Runzhi Wang Xinyi Li Yanxia Hu Zaikuan Zhang Jing Cai Jieru Yang Xiaosong Feng Suxia Ren Zengyi Huang Yajun Xie |
| author_sort | Fengling Shao |
| collection | DOAJ |
| description | Abstract High c-Myc protein accumulation contributes to the proliferation, invasion, and drug resistance in multiple cancer cells, but the underlying mechanism about c-Myc accumulation remains not to be elucidated. Here, we demonstrate that TTC36 promotes c-Myc protein accumulation in hepatocellular carcinoma cells, thereby driving the proliferation and sorafenib resistance in hepatocellular carcinoma cells. Ttc36 depletion disrupts the interaction between SET and PPP2R1A, consequently activating PP2A. Activated PP2A directly dephosphorylates p-c-MycS62 and activates GSK3β, relying on AKT, leading increased phosphorylation of p-c-MycT58, finally promotes FBXW7-mediated polyubiquitination and degradation of c-Myc. Inhibitors targeting GSK3β and PP2A effectively reverse the sorafenib resistance promoted by TTC36. These findings highlight the crucial role of TTC36 in c-Myc accumulation-caused proliferation and sorafenib resistance in HCC, providing a promising combination strategy for treating patients with c-Myc protein accumulation in advanced HCC. |
| format | Article |
| id | doaj-art-2db8d0b4c55841c99b441180d27679f9 |
| institution | OA Journals |
| issn | 2041-4889 |
| language | English |
| publishDate | 2025-04-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Cell Death and Disease |
| spelling | doaj-art-2db8d0b4c55841c99b441180d27679f92025-08-20T02:19:57ZengNature Publishing GroupCell Death and Disease2041-48892025-04-0116111210.1038/s41419-025-07663-4TTC36 promotes proliferation and drug resistance in hepatocellular carcinoma cells by inhibiting c-Myc degradationFengling Shao0Runzhi Wang1Xinyi Li2Yanxia Hu3Zaikuan Zhang4Jing Cai5Jieru Yang6Xiaosong Feng7Suxia Ren8Zengyi Huang9Yajun Xie10The Ministry of Education Key Laboratory of Laboratory Medical Diagnostics, the College of Laboratory Medicine, Chongqing Medical UniversityThe Ministry of Education Key Laboratory of Laboratory Medical Diagnostics, the College of Laboratory Medicine, Chongqing Medical UniversityThe Ministry of Education Key Laboratory of Laboratory Medical Diagnostics, the College of Laboratory Medicine, Chongqing Medical UniversitySchool of Life and Health Sciences, Hainan UniversityThe Ministry of Education Key Laboratory of Laboratory Medical Diagnostics, the College of Laboratory Medicine, Chongqing Medical UniversityCollege of Basic Medical Sciences, Harbin Medical UniversityThe Ministry of Education Key Laboratory of Laboratory Medical Diagnostics, the College of Laboratory Medicine, Chongqing Medical UniversityThe Ministry of Education Key Laboratory of Laboratory Medical Diagnostics, the College of Laboratory Medicine, Chongqing Medical UniversityDepartment of Cell Biology and Genetics, School of Basic Medical Sciences, Chongqing Medical UniversityDepartment of Cell Biology and Genetics, School of Basic Medical Sciences, Chongqing Medical UniversityThe Ministry of Education Key Laboratory of Laboratory Medical Diagnostics, the College of Laboratory Medicine, Chongqing Medical UniversityAbstract High c-Myc protein accumulation contributes to the proliferation, invasion, and drug resistance in multiple cancer cells, but the underlying mechanism about c-Myc accumulation remains not to be elucidated. Here, we demonstrate that TTC36 promotes c-Myc protein accumulation in hepatocellular carcinoma cells, thereby driving the proliferation and sorafenib resistance in hepatocellular carcinoma cells. Ttc36 depletion disrupts the interaction between SET and PPP2R1A, consequently activating PP2A. Activated PP2A directly dephosphorylates p-c-MycS62 and activates GSK3β, relying on AKT, leading increased phosphorylation of p-c-MycT58, finally promotes FBXW7-mediated polyubiquitination and degradation of c-Myc. Inhibitors targeting GSK3β and PP2A effectively reverse the sorafenib resistance promoted by TTC36. These findings highlight the crucial role of TTC36 in c-Myc accumulation-caused proliferation and sorafenib resistance in HCC, providing a promising combination strategy for treating patients with c-Myc protein accumulation in advanced HCC.https://doi.org/10.1038/s41419-025-07663-4 |
| spellingShingle | Fengling Shao Runzhi Wang Xinyi Li Yanxia Hu Zaikuan Zhang Jing Cai Jieru Yang Xiaosong Feng Suxia Ren Zengyi Huang Yajun Xie TTC36 promotes proliferation and drug resistance in hepatocellular carcinoma cells by inhibiting c-Myc degradation Cell Death and Disease |
| title | TTC36 promotes proliferation and drug resistance in hepatocellular carcinoma cells by inhibiting c-Myc degradation |
| title_full | TTC36 promotes proliferation and drug resistance in hepatocellular carcinoma cells by inhibiting c-Myc degradation |
| title_fullStr | TTC36 promotes proliferation and drug resistance in hepatocellular carcinoma cells by inhibiting c-Myc degradation |
| title_full_unstemmed | TTC36 promotes proliferation and drug resistance in hepatocellular carcinoma cells by inhibiting c-Myc degradation |
| title_short | TTC36 promotes proliferation and drug resistance in hepatocellular carcinoma cells by inhibiting c-Myc degradation |
| title_sort | ttc36 promotes proliferation and drug resistance in hepatocellular carcinoma cells by inhibiting c myc degradation |
| url | https://doi.org/10.1038/s41419-025-07663-4 |
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