Two somatic mutations in the androgen receptor N-terminal domain are oncogenic drivers in hepatocellular carcinoma
Abstract The androgen receptor (AR) plays an important role in male-dominant hepatocellular carcinoma, and specific acquired somatic mutations of AR have been observed in HCC patients. Our previous research have established the role of AR wild type as one of the key oncogenes in hepatocarcinogenesis...
| Main Authors: | , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2024-01-01
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| Series: | Communications Biology |
| Online Access: | https://doi.org/10.1038/s42003-023-05704-2 |
| _version_ | 1797362961500602368 |
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| author | Qian-Nan Ren Dan-Hui Huang Xiao-Nan Zhang Yue-Ning Wang Yu-Feng Zhou Mei-Yin Zhang Shuo-Cheng Wang Shi-Juan Mai De-Hua Wu Hui-Yun Wang |
| author_facet | Qian-Nan Ren Dan-Hui Huang Xiao-Nan Zhang Yue-Ning Wang Yu-Feng Zhou Mei-Yin Zhang Shuo-Cheng Wang Shi-Juan Mai De-Hua Wu Hui-Yun Wang |
| author_sort | Qian-Nan Ren |
| collection | DOAJ |
| description | Abstract The androgen receptor (AR) plays an important role in male-dominant hepatocellular carcinoma, and specific acquired somatic mutations of AR have been observed in HCC patients. Our previous research have established the role of AR wild type as one of the key oncogenes in hepatocarcinogenesis. However, the role of hepatic acquired somatic mutations of AR remains unknown. In this study, we identify two crucial acquired somatic mutations, Q62L and E81Q, situated close to the N-terminal activation function domain-1 of AR. These mutations lead to constitutive activation of AR, both independently and synergistically with androgens, making them potent driver oncogene mutations. Mechanistically, these N-terminal AR somatic mutations enhance de novo lipogenesis by activating sterol regulatory element-binding protein-1 and promote glycogen accumulation through glycogen phosphorylase, brain form, thereby disrupting the AMPK pathway and contributing to tumorigenesis. Moreover, the AR mutations show sensitivity to the AMPK activator A769662. Overall, this study establishes the role of these N- terminal hepatic mutations of AR as highly malignant oncogenic drivers in hepatocarcinogenesis and highlights their potential as therapeutic targets for patients harboring these somatic mutations. |
| first_indexed | 2024-03-08T16:14:04Z |
| format | Article |
| id | doaj.art-27788ad823be4a8ebdef13bb796654ba |
| institution | Directory Open Access Journal |
| issn | 2399-3642 |
| language | English |
| last_indexed | 2024-03-08T16:14:04Z |
| publishDate | 2024-01-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Communications Biology |
| spelling | doaj.art-27788ad823be4a8ebdef13bb796654ba2024-01-07T12:39:55ZengNature PortfolioCommunications Biology2399-36422024-01-017111610.1038/s42003-023-05704-2Two somatic mutations in the androgen receptor N-terminal domain are oncogenic drivers in hepatocellular carcinomaQian-Nan Ren0Dan-Hui Huang1Xiao-Nan Zhang2Yue-Ning Wang3Yu-Feng Zhou4Mei-Yin Zhang5Shuo-Cheng Wang6Shi-Juan Mai7De-Hua Wu8Hui-Yun Wang9Department of Radiation Oncology, Nanfang Hospital, Southern Medical UniversityDepartment of Respiratory and Critical Care Medicine, Chronic Airways Diseases Laboratory, Nanfang Hospital, Southern Medical UniversityDepartment of Radiation Oncology, Nanfang Hospital, Southern Medical UniversityState Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-Sen University Cancer CenterState Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-Sen University Cancer CenterState Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-Sen University Cancer CenterState Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-Sen University Cancer CenterState Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-Sen University Cancer CenterDepartment of Radiation Oncology, Nanfang Hospital, Southern Medical UniversityState Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-Sen University Cancer CenterAbstract The androgen receptor (AR) plays an important role in male-dominant hepatocellular carcinoma, and specific acquired somatic mutations of AR have been observed in HCC patients. Our previous research have established the role of AR wild type as one of the key oncogenes in hepatocarcinogenesis. However, the role of hepatic acquired somatic mutations of AR remains unknown. In this study, we identify two crucial acquired somatic mutations, Q62L and E81Q, situated close to the N-terminal activation function domain-1 of AR. These mutations lead to constitutive activation of AR, both independently and synergistically with androgens, making them potent driver oncogene mutations. Mechanistically, these N-terminal AR somatic mutations enhance de novo lipogenesis by activating sterol regulatory element-binding protein-1 and promote glycogen accumulation through glycogen phosphorylase, brain form, thereby disrupting the AMPK pathway and contributing to tumorigenesis. Moreover, the AR mutations show sensitivity to the AMPK activator A769662. Overall, this study establishes the role of these N- terminal hepatic mutations of AR as highly malignant oncogenic drivers in hepatocarcinogenesis and highlights their potential as therapeutic targets for patients harboring these somatic mutations.https://doi.org/10.1038/s42003-023-05704-2 |
| spellingShingle | Qian-Nan Ren Dan-Hui Huang Xiao-Nan Zhang Yue-Ning Wang Yu-Feng Zhou Mei-Yin Zhang Shuo-Cheng Wang Shi-Juan Mai De-Hua Wu Hui-Yun Wang Two somatic mutations in the androgen receptor N-terminal domain are oncogenic drivers in hepatocellular carcinoma Communications Biology |
| title | Two somatic mutations in the androgen receptor N-terminal domain are oncogenic drivers in hepatocellular carcinoma |
| title_full | Two somatic mutations in the androgen receptor N-terminal domain are oncogenic drivers in hepatocellular carcinoma |
| title_fullStr | Two somatic mutations in the androgen receptor N-terminal domain are oncogenic drivers in hepatocellular carcinoma |
| title_full_unstemmed | Two somatic mutations in the androgen receptor N-terminal domain are oncogenic drivers in hepatocellular carcinoma |
| title_short | Two somatic mutations in the androgen receptor N-terminal domain are oncogenic drivers in hepatocellular carcinoma |
| title_sort | two somatic mutations in the androgen receptor n terminal domain are oncogenic drivers in hepatocellular carcinoma |
| url | https://doi.org/10.1038/s42003-023-05704-2 |
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