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Nature Medicine 13, 1060 - 1069 (2007)
Published online: 12 August 2007 | doi:10.1038/nm1621

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

Liyong Zhang1,2,5, Michael S Anglesio3,5, Maureen O'Sullivan3, Fan Zhang3, Ge Yang2, Renu Sarao1,2, Mai P Nghiem1,2, Shane Cronin1, Hiromitsu Hara1, Nataliya Melnyk3, Liheng Li3, Teiji Wada1, Peter P Liu2, Jason Farrar4, Robert J Arceci4, Poul H Sorensen3 & Josef M Penninger1

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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