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Cancer Prev Res (Phila). 2013 Apr;6(4):290-8. doi: 10.1158/1940-6207.CAPR-12-0449-T. Epub 2013 Jan 30.

Defining the role of histone deacetylases in the inhibition of mammary carcinogenesis by dietary energy restriction (DER): effects of suberoylanilide hydroxamic acid (SAHA) and DER in a rat model.

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1
Cancer Prevention Laboratory, Colorado State University, 1173 Campus Delivery, Fort Collins, CO 80523, USA.

Abstract

Dietary energy restriction (DER) inhibits experimentally induced mammary cancer, an effect accompanied by elevated levels of silent information regulator 2 (SIRT1), a class III histone deacetylase (HDAC). However, the effect of DER on targets of other classes of HDACs has not been reported, a highly relevant issue given evidence that HDAC induction favors the development of cancer and tumor growth. Experiments were carried out to determine whether suberoylanilide hydroxamic acid (SAHA), a histone deacetylase inhibitor with broad activity, would affect the anti-cancer activity of DER. Female Sprague Dawley rats (n = 30/group) were injected with 1-methyl-1-nitrosourea (50 mg/kg) at 21 days of age and 7 days thereafter were randomized to groups fed: (i) control diet (AIN-93G), (ii) 0.1% SAHA (w/w), (iii) 40% DER, or (iv) 0.1% SAHA + 40% DER. An additional group was fed 0.1% SAHA + 40%DER for 5 weeks and released to control diet for 3 weeks. DER significantly reduced mammary cancer incidence, multiplicity, and cancer burden and prolonged cancer latency (P < 0.01). Cancer inhibition was maintained in SAHA + DER, despite evidence that histone (H2A(Lys9), H2B(Lys5), and H4(Lys5/8/12/16), but not H3(Lys9); P < 0.001) and non-histone protein deacetylation (p53(Lys373) and p53(Lys382); P < 0.001) induced by DER was reversed by SAHA. This indicates that the inhibition of DER of cancer is not dependent on HDAC induction. After releasing rats from DER + SAHA, cancer multiplicity remained lower than control (P < 0.05), consistent with apoptosis-mediated cell deletion. These findings support further investigation of the hypothesis that HDAC induction by DER blunts its anti-carcinogenic impact.

PMID:
23365133
PMCID:
PMC4636215
DOI:
10.1158/1940-6207.CAPR-12-0449-T
[Indexed for MEDLINE]
Free PMC Article
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