Epigenetic modulators, particularly
histone deacetylases (HDACs), are valid targets for
cancer prevention and
therapy. Recent studies report that HDAC2 overexpression is associated with colon
tumor progression and is a potential target for
colon cancer prevention. This study tested chemopreventive and dose-response effects of Ohio State University HDAC42 (OSU-HDAC42), a selective HDAC2 inhibitor, using a rat colon
carcinogenesis model to assess
aberrant crypt foci inhibition and a
familial adenomatous polyposis model to assess intestinal
tumor inhibition. Colonic
aberrant crypt foci were induced by
azoxymethane (AOM) (15 mg/kg
body weight, once-weekly
subcutaneous injections at 8 and 9 weeks age). One week after AOM treatment, groups of rats were fed an AIN-76A diet containing 0, 75, 150, and 300 ppm OSU-HDAC42 for 8 weeks, and colonic
aberrant crypt foci were evaluated. To assess the inhibitory effect of OSU-HDAC42 on small-
intestinal polyps and colon
tumor growth, 6-week-old male C57Bl/6J-APC(min/+)mice were fed an AIN-76A diet containing 150 ppm OSU-HADC42 or 300 ppm pan-
HDAC inhibitor suberoylanilide hydroxyamic
acid (SAHA) for 80 days. Our results demonstrate that dietary OSU-HDAC42 produced dose-dependent inhibition of AOM-induced colonic
aberrant crypt foci formation (13-50%; P < 0.01 to < 0.0001) and reduced multiple crypts with ≥ 4 crypts per focus (25-57%; P < 0.01 to < 0.0001) in F344 rats. Our findings show that 150 ppm OSU-HDAC42 significantly inhibited small-
intestinal polyps (>46%; P < 0.001), with
polyp size measuring >1 mm (P < 0.001), and colon
tumors (>26%) in APC(min/+)mice, whereas 300 ppm SAHA showed nonsignificant inhibition. Mice fed 150 ppm OSU-HDAC42 had significantly decreased HDAC2,
proliferating cell nuclear antigen,
B cell lymphoma 2,
cyclin-dependent kinase 2, and cell division cycle homolog 25C expression levels and increased p53 expression levels. These observations demonstrate the chemopreventive efficacy of OSU-HDAC42 against chemically induced and polyposis models of intestinal
tumorigenesis.