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

Liyong Zhang, Michael S. Anglesio, Maureen O'Sullivan, Fan Zhang, Ge Yang, Renu Sarao, Mai P. Nghiem, Shane Cronin, Hiromitsu Hara, Nataliya Melnyk, Liheng Li, Teiji Wada, Peter P. Liu, Jason Farrar, Robert J. Arceci, Poul H. Sorensen, Josef M. Penninger

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish (US)
Pages (from-to)1060-1069
Number of pages10
JournalNature medicine
Volume13
Issue number9
DOIs
StatePublished - Sep 2007

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Fingerprint Dive into the research topics of 'The E3 ligase HACE1 is a critical chromosome 6q21 tumor suppressor involved in multiple cancers'. Together they form a unique fingerprint.

Cite this