Reduced body size and decreased intestinal tumor rates in HDAC2-mutant mice

Stephan Zimmermann, Franz Kiefer, Michela Prudenziati, Carmen Spiller, Jens Hansen, Thomas Floss, Wolfgang Wurst, Saverio Minucci, Martin Göttlicher

Research output: Contribution to journalArticlepeer-review

Abstract

Histone deacetylases (HDAC) reverse the acetylation of histone and nonhistone proteins and thereby modulate chromatin structure and function of nonhistone proteins. Many tumor cell lines and experimental tumors respond to HDAC inhibition. To assess the role of an individual HDAC isoenzyme in physiology and tumor development, HDAC2-mutant mice were generated from a gene trap embryonic stem cell clone. These mice express a catalytically inactive fusion protein of the NH2-terminal part of HDAC2 and β-galactosidase,which fails to integrate into corepressor complexes with mSin3B. They are the first class 1 HDAC mutant mice that are viable although they are ∼25% smaller than their littermates. Cell number and thickness of intestinal mucosa are reduced. Mutant embryonic fibroblasts fail to respond to insulin-like growth factor I (IGF) by the IGF-I-induced increase in cell number observed in wild-type cells. These data suggest a novel link between HDACs and IGF-I-dependent responses. Crossing of HDAC2-mutant with tumor-prone APC min mice revealed tumor rates that are lower in HDAC2-deficient mice by 10% to 100% depending on segment of the gut and sex of the mice. These mice provide evidence that the key functions of HDAC2, although not essential for survival of the organism, play a rate-limiting role for tumor development in vivo.

Original languageEnglish
Pages (from-to)9047-9054
Number of pages8
JournalCancer Research
Volume67
Issue number19
DOIs
Publication statusPublished - Oct 1 2007

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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