Kinesin family member 18B activates mTORC1 signaling via actin gamma 1 to promote the recurrence of human hepatocellular carcinoma

Qian Li; Mengqing Sun; Yao Meng; Mengqing Feng; Menglan Wang; Cunjie Chang; Heng Dong; Fangtian Bu; Chao Xu; Jing Liu; Qi Ling; Yiting Qiao; Jianxiang Chen

doi:10.1038/s41389-023-00499-7

Kinesin family member 18B activates mTORC1 signaling via actin gamma 1 to promote the recurrence of human hepatocellular carcinoma

Oncogenesis. 2023 Nov 13;12(1):54. doi: 10.1038/s41389-023-00499-7.

Authors

Qian Li^{1

2}, Mengqing Sun^{1

2}, Yao Meng^{1

2}, Mengqing Feng^{1

2}, Menglan Wang^{1

2}, Cunjie Chang^{1

2}, Heng Dong^{1

2}, Fangtian Bu^{1

2}, Chao Xu^{1

2}, Jing Liu¹, Qi Ling³, Yiting Qiao^{4

5

6}, Jianxiang Chen^{7

8

9}

Affiliations

¹ School of Pharmacy and Department of Hepatology, the Affiliated Hospital of Hangzhou Normal University, Hangzhou Normal University, Hangzhou, 311121, P. R. China.
² Key Laboratory of Elemene Class Anti-Cancer Chinese Medicines; Engineering Laboratory of Development and Application of Traditional Chinese Medicines; Collaborative Innovation Center of Traditional Chinese Medicines of Zhejiang Province, Hangzhou Normal University, Hangzhou, Zhejiang, 311121, P. R. China.
³ Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, NHC Key Laboratory of Combined Multi-organ Transplantation, Key Laboratory of Organ Transplantation, Research Center for Diagnosis and Treatment of Hepatobiliary Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310003, P. R. China. lingqi@zju.edu.cn.
⁴ School of Pharmacy and Department of Hepatology, the Affiliated Hospital of Hangzhou Normal University, Hangzhou Normal University, Hangzhou, 311121, P. R. China. yitingqiao@zju.edu.cn.
⁵ Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, NHC Key Laboratory of Combined Multi-organ Transplantation, Key Laboratory of Organ Transplantation, Research Center for Diagnosis and Treatment of Hepatobiliary Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310003, P. R. China. yitingqiao@zju.edu.cn.
⁶ Jinan Microecological Biomedicine Shandong Laboratory, Jinan, Shandong, 250000, P. R. China. yitingqiao@zju.edu.cn.
⁷ School of Pharmacy and Department of Hepatology, the Affiliated Hospital of Hangzhou Normal University, Hangzhou Normal University, Hangzhou, 311121, P. R. China. chenjx@hznu.edu.cn.
⁸ Key Laboratory of Elemene Class Anti-Cancer Chinese Medicines; Engineering Laboratory of Development and Application of Traditional Chinese Medicines; Collaborative Innovation Center of Traditional Chinese Medicines of Zhejiang Province, Hangzhou Normal University, Hangzhou, Zhejiang, 311121, P. R. China. chenjx@hznu.edu.cn.
⁹ Laboratory of Cancer Genomics, Division of Cellular and Molecular Research, National Cancer Centre, Singapore, 169610, Singapore. chenjx@hznu.edu.cn.

Abstract

The mechanistic target of rapamycin complex 1 (mTORC1) signaling pathway is frequently reported to be hyperactivated in hepatocellular carcinoma (HCC) and contributes to HCC recurrence. However, the underlying regulatory mechanisms of mTORC1 signaling in HCC are not fully understood. In the present study, we found that the expression of kinesin family member 18B (KIF18B) was positively correlated with mTORC1 signaling in HCC, and the upregulation of KIF18B and p-mTOR was associated with a poor prognosis and HCC recurrence. Utilizing in vitro and in vivo assays, we showed that KIF18B promoted HCC cell proliferation and migration through activating mTORC1 signaling. Mechanistically, we identified Actin gamma 1 (γ-Actin) as a binding partner of KIF18B. KIF18B and γ-Actin synergistically modulated lysosome positioning, promoted mTORC1 translocation to lysosome membrane, and prohibited p70 S6K from entering lysosomes for degradation, which finally led to the enhancement of mTORC1 signaling transduction. Moreover, we found that KIF18B was a direct target of Forkhead box M1, which explains the potential mechanism of KIF18B overexpression in HCC. Our study highlights the potential of KIF18B as a therapeutic target for the treatment of HCC.

Abstract

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