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HFE promotes mitotic cell division through recruitment of cytokinetic abscission machinery in hepatocellular carcinoma

Abstract

HFE (Hemochromatosis) is a conventional iron level regulator and its loss of function due to gene mutations increases the risk of cancers including hepatocellular carcinoma (HCC). Likewise, studies focusing on HFE overexpression in cancers are all limited to linking up these events as a consequence of iron level deregulation. No study has explored any iron unrelated role of HFE in cancers. Here, we first reported HFE as an oncogene in HCC and its undescribed function on promoting abscission in cytokinesis during mitotic cell division, independent of its iron-regulating ability. Clinical analyses revealed HFE upregulation in tumors linking to large tumor size and poor prognosis. Functionally and mechanistically, HFE promoted cytokinetic abscission via facilitating ESCRT abscission machinery recruitment to the abscission site through signaling a novel HFE/ALK3/Smads/LIF/Hippo/YAP/YY1/KIF13A axis. Pharmacological blockage of HFE signaling axis impeded tumor phenotypes in vitro and in vivo. Our data on HFE-driven HCC unveiled a new mechanism utilized by cancer cells to propel rapid cell division. This study also laid the groundwork for tumor intolerable therapeutics development given the high cytokinetic dependency of cancer cells and their vulnerability to cytokinetic blockage.

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Fig. 1: HFE overexpression correlates with poor prognosis of HCC patients.
Fig. 2: HFE promotes HCC cell proliferation, growth and apoptosis evasion.
Fig. 3: HFE enhances HCC tumor growth in vivo.
Fig. 4: HFE loss arrests HCC cells in G2/M phase of cell cycle accompanying cytokinesis defect, supernumerary centrosomes and multipolar spindles.
Fig. 5: HFE suppression-induced microtubule derangement and cytokinetic bridge deformation limits abscission factor CHMP1B recruitment in dividing HCC cells.
Fig. 6: HFE interacts with ALK3 and transduces through Smads, LIF, Hippo/YAP.
Fig. 7: Positive correlation of HFE and KIF13A in HCC.
Fig. 8: Pharmacological inhibition of HFE/ALK3/Smads/LIF/Hippo/YAP/YY1/KIF13A axis using verteporfin abolishes HFE-induced tumor phenotypes in vitro and in vivo.

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Acknowledgements

We would like to thank Dr Lui Ng from Department of Surgery, The University of Hong Kong for providing anti-Smad2/3 antibodies.

Funding

This study was financially supported by Theme-based Research Scheme (T42-103/16-N and T12-703/19-R) of the Research Grants Council, Hong Kong and the Health@InnoHK program of the Innovation and Technology Commission of the Hong Kong SAR Government.

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PD, ZC, BL, and NPL: study concept and design; PD, ZC, AKC, MWC, CHA: acquisition of data; PD, ZC, YZ, AKC, MWC, CHA: analysis and interpretation of data; PD, ZC, AKC, MWC, NPL: drafting of the manuscript; CHA, KM, NPL: critical revision of the manuscript for important intellectual content; PD, ZC, CHA: statistical analysis; CML, KM, NPL: obtained funding; AKC, MWC, CHA, WKS, TTC, KM, NPL: administrative, technical, or material support; WKS, TTC, CML, KM, NPL: study supervision.

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Correspondence to Kwan Man or Nikki P. Lee.

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Dong, P., Cai, Z., Li, B. et al. HFE promotes mitotic cell division through recruitment of cytokinetic abscission machinery in hepatocellular carcinoma. Oncogene 41, 4185–4199 (2022). https://doi.org/10.1038/s41388-022-02419-2

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