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 NH 2 -terminal part of HDAC2 and B-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 f25% 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.

Inappropriate control of expression of genetic information is the cause of many forms of cancer. Aberrant transcriptional repression by recruitment of histone deacetylases (HDACs) is a key step in pathogenesis of myeloid leukemia. We recently reported that development of colonic cancer involves alterations in the transcriptional repression machinery by increased expression of HDAC2 upon loss of the APC tumor suppressor. Increased expression of HDAC2 is essential for prevention of apoptosis of HT-29 colonic cancer cells. We now discuss whether HDAC2 also plays a role for aberrant cell cycle regulation and expression of the p21(Cip/Waf) cell cycle inhibitor. Whereas inhibition of HDACs by valproic acid or trichostatin A increases p21 expression, selective interference with HDAC2 by siRNA transfection or reconstitution of wildtype APC does not affect p21 expression. Likewise, treatment of HT-29 cells with the HDAC inhibitor valproic acid leads to a moderate inhibition of cell cycle progression in the G1 phase whereas interference with HDAC2 expression does not. Thus, HDAC2 appears to serve a preferential role in the prevention of apoptosis and not in cell cycle control similar to the specific importance of HDAC1 for cell cycle regulation or HDAC 9 for the stress response of the heart.

No abstract

No abstract

No abstract