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The E3 ligase HACE1 is a critical chromosome 6q21 tumor suppressor involved in multiple cancers

Abstract

Transformation and cancer growth are regulated by the coordinate actions of oncogenes and tumor suppressors. Here, we show that the novel E3 ubiquitin ligase HACE1 is frequently downregulated in human tumors and maps to a region of chromosome 6q21 implicated in multiple human cancers. Genetic inactivation of HACE1 in mice results in the development of spontaneous, late-onset cancer. A second hit from either environmental triggers or genetic heterozygosity of another tumor suppressor, p53, markedly increased tumor incidence in a Hace1-deficient background. Re-expression of HACE1 in human tumor cells directly abrogates in vitro and in vivo tumor growth, whereas downregulation of HACE1 via siRNA allows non-tumorigenic human cells to form tumors in vivo. Mechanistically, the tumor-suppressor function of HACE1 is dependent on its E3 ligase activity and HACE1 controls adhesion-dependent growth and cell cycle progression during cell stress through degradation of cyclin D1. Thus, HACE1 is a candidate chromosome 6q21 tumor-suppressor gene involved in multiple cancers.

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Figure 1: Loss of HACE1 expression by epigenetic modification in human Wilms' tumor.
Figure 2: Reduced HACE1 expression in multiple human tumors and spontaneous tumor formation in Hace1 mutant mice.
Figure 3: Hace1 mutant mice are susceptible to urethane-induced lung cancer.
Figure 4: Cooperativity between p53 and HACE1 in tumor suppression.
Figure 5: HACE1 controls growth and tumorigenesis of transformed human cancer cells.
Figure 6: HACE1 controls anchorage-dependent growth and cyclin D1 expression.
Figure 7: HACE1 modulates cell proliferation pathways via cyclin D1 degradation.

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Acknowledgements

We thank P. Grundy and the Children's Oncology Group as well as the Cooperative Human Tissue Network (CHTN) for providing clinical Wilms' tumor samples for this study; A. Brooks-Wilson and M. Marra for HACE1 sequencing assistance; R. Kandel and D. Holmyard for help with electron microscopy of the sarcoma samples; D. Bouchard and N.-J. Chen for assistance with FACS, M. Bowden and M. Gleave for assistance with nude mouse studies; and V. Evdokimova, T. Zoranovic, K. Kuba, N. Joza, A. Oliveira-dos Santos, M. Crackower, I. Kozieradski, T. Nakashima, H. Jones Taggart, M. Cheung, M. Rangachari, Y. Liu, M. Sun and M. Pollard for discussions, technical help and reagents. The GFP-tagged activated Ki-Ras plasmid was provided by R. Kay, Terry Fox Laboratory, British Columbia Cancer Research Centre. This work was supported by the National Cancer Institute of Canada (NCIC) (to P.H.S.), a Canadian Institutes of Health Research (CIHR) post-doctoral fellowship (to F.Z.), the Institute for Molecular Biotechnology of the Austrian Academy of Sciences (IMBA), the Jubilaeumsfonds of the Austrian National Bank, GEN-AU and an EU Excellence grant to J.M.P.

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Contributions

L.Z. made Hace1 mutant mice in the laboratory of J.M.P. and later in the laboratory of P.P.L. and analyzed the tumors in vivo with significant help from G.Y., R.S., M.P.N., S.C., H.H., T.W. and P.P.L. M.S.A. performed most of the in vitro cell line experiments, with significant assistance from F.Z., N.M. and L.L. M.O. and P.H.S. are trained pathologists and assessed the tumors histologically. J.F. and R.J.A. did all methylation studies reported in the paper. P.H.S. and J.M.P. supervised and initiated the project from the outset and together wrote the paper.

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Correspondence to Poul H Sorensen or Josef M Penninger.

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One coauthor, P.S., has applied for a U.S. patent on the HACE1 protein.

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Supplementary Methods, Supplementary Figs. 1–12, Supplementary Table 1 and Supplementary References (PDF 10572 kb)

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Zhang, L., Anglesio, M., O'Sullivan, M. et al. The E3 ligase HACE1 is a critical chromosome 6q21 tumor suppressor involved in multiple cancers. Nat Med 13, 1060–1069 (2007). https://doi.org/10.1038/nm1621

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