@article{6fabe368efff47dcb5fd50de81876aad,
title = "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.",
author = "Liyong Zhang and Anglesio, {Michael S.} and Maureen O'Sullivan and Fan Zhang and Ge Yang and Renu Sarao and Nghiem, {Mai P.} and Shane Cronin and Hiromitsu Hara and Nataliya Melnyk and Liheng Li and Teiji Wada and Liu, {Peter P.} and Jason Farrar and Arceci, {Robert J.} and Sorensen, {Poul H.} and Penninger, {Josef M.}",
note = "Funding Information: We thank P. Grundy and the Children{\textquoteright}s Oncology Group as well as the Cooperative Human Tissue Network (CHTN) for providing clinical Wilms{\textquoteright} 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.",
year = "2007",
month = sep,
doi = "10.1038/nm1621",
language = "English (US)",
volume = "13",
pages = "1060--1069",
journal = "Nature medicine",
issn = "1078-8956",
publisher = "Nature Publishing Group",
number = "9",
}