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Targeting anillin inhibits tumorigenesis and tumor growth in hepatocellular carcinoma via impairing cytokinesis fidelity

Oncogene volume 41, pages 3118–3130 (2022)Cite this article

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Abstract

Targeting cytokinesis can suppress tumor growth by blocking cell division and promoting apoptosis. We aimed to characterize key cytokinesis regulator in hepatocellular carcinoma (HCC) progression, providing insights into identifying promising HCC therapeutic targets. The unbiased bioinformatic screening identified Anillin actin binding protein (ANLN) as a critical cytokinesis regulator involved in HCC development. Functional assay demonstrated that knockdown of ANLN inhibited HCC growth by inducing cytokinesis failure and DNA damage, leading to multinucleation and mitotic catastrophe. Mechanistically, ANLN acts as a scaffold to strengthen interaction between RACGAP1 and PLK1. ANLN promotes PLK1-mediated RACGAP1 phosphorylation and RhoA activation to ensure cytokinesis fidelity. To explore the function of ANLN in HCC tumorigenesis, we hydrodynamically transfected c-Myc and NRAS plasmids into Anln+/+, Anln+/−, and Anln−/− mice through tail vein injection. Hepatic Anln ablation significantly impaired c-Myc/NRAS-driven hepatocarcinogenesis. Moreover, enhanced hepatic polyploidization was observed in Anln ablation mice, manifesting as increasing proportion of cellular and nuclear polyploidy. Clinically, ANLN is upregulated in human HCC tissues and high level of ANLN is correlated with poor patients’ prognosis. Additionally, the proportion of cellular polyploidy decreases during HCC progression and ANLN level is significantly correlated with cellular polyploidy proportion in human HCC samples. In conclusion, ANLN is identified as a key cytokinesis regulator contributing to HCC initiation and progression. Our findings revealed a novel mechanism of ANLN in the regulation of cytokinesis to promote HCC tumorigenesis and growth, suggesting targeting ANLN to inhibit cytokinesis may be a promising therapeutic strategy for HCC.

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Fig. 1: ANLN is upregulated in HCC tumor tissues and high level of ANLN is correlated with poor prognosis in patients with HCC.
Fig. 2: ANLN contributes to HCC growth in vitro and in vivo.
Fig. 3: Knockdown of ANLN induced cytokinesis failure and DNA damage, leading to mitotic catastrophe and apoptosis.
Fig. 4: ANLN promoted phosphorylation of RACGAP1 through enhancing the interaction between RACGAP1 and PLK1 during cytokinesis.
Fig. 5: RACGAP1 phosphorylation reversed ANLN knockdown-induced cytokinesis failure and RhoA inactivation.
Fig. 6: Genetic deletion of Anln prevents tumor initiation in c-Myc/NRAS-driven HCC tumorigenesis in mice.
Fig. 7: The correlation between ANLN level and ploidy status in mice and human samples.
Fig. 8: A model depicting underlying mechanism of ANLN-mediated cytokinesis in promoting HCC progression.

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Acknowledgements

This study was supported by the grants from the Key Research and Development Plan of Zhejiang Province (No. 2020C04003), the National Natural Science Foundation of China (No. 81870434 and No. 82070652), the Innovative Research Groups of National Natural Science Foundation of China (No. 81721091) and the Key Research and Development Plan of Zhejiang Province (No. 2019C03050).

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  1. These authors contributed equally: Jian Chen, Zequn Li, Xing Jia

Authors and Affiliations

  1. Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China

    Jian Chen, Zequn Li, Xing Jia, Wenfeng Song, Hao Wu, Hai Zhu, Xingxin Zhu, Guangyuan Song, Haijiang Dong, Suchen Bian, Shuo Wang, Haiyang Xie, Shusen Zheng & Penghong Song

  2. NHC Key Laboratory of Combined Multi-organ Transplantation, Hangzhou, China

    Jian Chen, Zequn Li, Xing Jia, Wenfeng Song, Hao Wu, Hai Zhu, Xingxin Zhu, Guangyuan Song, Haijiang Dong, Suchen Bian, Yongchao Zhao, Haiyang Xie, Shusen Zheng & Penghong Song

  3. Key Laboratory of the diagnosis and treatment of organ Transplantation, Research Unit of Collaborative Diagnosis and Treatment For Hepatobiliary and Pancreatic Cancer, Chinese Academy of Medical Sciences (2019RU019), Hangzhou, China

    Jian Chen, Zequn Li, Xing Jia, Wenfeng Song, Hao Wu, Hai Zhu, Xingxin Zhu, Guangyuan Song, Haijiang Dong, Suchen Bian, Haiyang Xie, Shusen Zheng & Penghong Song

  4. Key Laboratory of Organ Transplantation, Research Center for Diagnosis and Treatment of Hepatobiliary Diseases, Hangzhou, Zhejiang Province, China

    Jian Chen, Zequn Li, Xing Jia, Wenfeng Song, Hao Wu, Hai Zhu, Xingxin Zhu, Guangyuan Song, Haijiang Dong, Suchen Bian, Haiyang Xie, Shusen Zheng & Penghong Song

  5. Division of Breast Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China

    Zefeng Xuan

  6. Division of Thyroid Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China

    Yehui Du

  7. Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, China

    Yongchao Zhao

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Contributions

JC, PS, and SZ designed the study. JC, ZL, WS, HW, and XJ performed the experiments. HZ and XZ performed the bioinformatic analysis. XJ, SB, GS, HD, and SW performed the in vivo experiments. JC and HW analyzed the data. JC, HX, PS, and SZ wrote the paper. ZX, YD, ZL, YZ, and XJ critically reviewed and revised the paper. All authors read and approved the final version of the paper.

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Correspondence to Shusen Zheng or Penghong Song.

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Chen, J., Li, Z., Jia, X. et al. Targeting anillin inhibits tumorigenesis and tumor growth in hepatocellular carcinoma via impairing cytokinesis fidelity. Oncogene 41, 3118–3130 (2022). https://doi.org/10.1038/s41388-022-02274-1

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