TSC/mTORC1 mediates mTORC2/AKT1 signaling in c-MYC–induced murine hepatocarcinogenesis via centromere protein M

Activated mTORC2/AKT signaling plays a role in hepatocellular carcinoma (HCC). Research has shown that TSC/mTORC1 and FOXO1 are distinct downstream effectors of AKT signaling in liver regeneration and metabolism. However, the mechanisms by which these pathways mediate mTORC2/AKT activation in HCC are not yet fully understood. Amplification and activation of c-MYC are key molecular events in HCC. In this study, we explored the roles of tuberous sclerosis complex/mTORC1 (TSC/mTORC1) and FOXO1 as downstream effectors of mTORC2/AKT1 in c-MYC-induced hepatocarcinogenesis. Using various genetic approaches in mice, we found that manipulating the FOXO pathway had a minimal effect on c-MYC-induced HCC. In contrast, loss of mTORC2 inhibited c-MYC-induced HCC, an effect that was completely reversed by ablation of TSC2, which activated mTORC1. Additionally, we discovered that p70/RPS6 and 4EBP1/eIF4E acted downstream of mTORC1, regulating distinct molecular pathways. Notably, the 4EBP1/eIF4E cascade is crucial for cell proliferation and glycolysis in c-MYC-induced HCC. We also identified centromere protein M (CENPM) as a downstream target of the TSC2/mTORC1 pathway in c-MYC-driven hepatocarcinogenesis, and its ablation entirely inhibited c-MYC-dependent HCC formation. Our findings demonstrate that the TSC/mTORC1/CENPM pathway, rather than the FOXO cascade, is the primary signaling pathway regulating c-MYC-driven hepatocarcinogenesis. Targeting CENPM holds therapeutic potential for treating c-MYC-driven HCC.

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Publication Details

Journal
Journal of Clinical Investigation
Published
2024-09-26
DOI
https://doi.org/10.1172/jci174415
Citations
8
Primary Topic
PI3K/AKT/mTOR signaling in cancer
Type
article
Field-Weighted Citation Impact
1.87

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article

TSC/mTORC1 mediates mTORC2/AKT1 signaling in c-MYC–induced murine hepatocarcinogenesis via centromere protein M

Guoteng Qiu, Nianyong Chen, Haichuan Wang, Matthias Evert et al.
8 citations
Journal of Clinical Investigation
PI3K/AKT/mTOR signaling in cancer
1.87
article

TSC/mTORC1 mediates mTORC2/AKT1 signaling in c-MYC–induced murine hepatocarcinogenesis via centromere protein M

Guoteng Qiu, Nianyong Chen, Haichuan Wang, Matthias Evert, Shanshan Deng, Xinhua Song, Shu Zhang, Yi Zhou, Xin Chen, Guofei Cui, Shumei Lin, Xue Wang, Diego F. Calvisi, Andrew Yonemura, Hongwei Xu, Youping Deng, Meng Xu, Joanne Chun, Zijing Xu, Jingwen Wang
article en
8 citations

Abstract

Activated mTORC2/AKT signaling plays a role in hepatocellular carcinoma (HCC). Research has shown that TSC/mTORC1 and FOXO1 are distinct downstream effectors of AKT signaling in liver regeneration and metabolism. However, the mechanisms by which these pathways mediate mTORC2/AKT activation in HCC are not yet fully understood. Amplification and activation of c-MYC are key molecular events in HCC. In this study, we explored the roles of tuberous sclerosis complex/mTORC1 (TSC/mTORC1) and FOXO1 as downstream effectors of mTORC2/AKT1 in c-MYC-induced hepatocarcinogenesis. Using various genetic approaches in mice, we found that manipulating the FOXO pathway had a minimal effect on c-MYC-induced HCC. In contrast, loss of mTORC2 inhibited c-MYC-induced HCC, an effect that was completely reversed by ablation of TSC2, which activated mTORC1. Additionally, we discovered that p70/RPS6 and 4EBP1/eIF4E acted downstream of mTORC1, regulating distinct molecular pathways. Notably, the 4EBP1/eIF4E cascade is crucial for cell proliferation and glycolysis in c-MYC-induced HCC. We also identified centromere protein M (CENPM) as a downstream target of the TSC2/mTORC1 pathway in c-MYC-driven hepatocarcinogenesis, and its ablation entirely inhibited c-MYC-dependent HCC formation. Our findings demonstrate that the TSC/mTORC1/CENPM pathway, rather than the FOXO cascade, is the primary signaling pathway regulating c-MYC-driven hepatocarcinogenesis. Targeting CENPM holds therapeutic potential for treating c-MYC-driven HCC.

Journal of Clinical InvestigationVol. 134(22)
University of Hawaiʻi at Mānoa (US), Hawaii Department of Health (US), University of Hawaii System (US), University of California, San Francisco (US), Sichuan University (CN), National Cancer Center (US), West China Hospital of Sichuan University (CN), Cancer Center of Hawaii (US), General Department of Preventive Medicine (VN), Sichuan Cancer Hospital (CN), First Affiliated Hospital of Xi'an Jiaotong University (CN), Second Affiliated Hospital of Xi'an Jiaotong University (CN), Beijing Hospital of Traditional Chinese Medicine (CN), University of Hawaii Cancer Center, University of Regensburg (DE)
National Natural Science Foundation of China, National Institutes of Health
Openalex Percentile: Top 14%
PI3K/AKT/mTOR signaling in cancer
1.87
DOIOpen Access PDFOpenAlex
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