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

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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.

Authors

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