Defining the Role of Histone Deacetylases in Inhibition of Mammary Carcinogenesis by Dietary Energy Restriction:Effects of SAHA and DER in Rat Model
Menée à l'aide d'un modèle murin, cette étude analyse les effets d'une restriction énergétique alimentaire, complétée par l'administration d'acide suberoylanilide hydroxamique, un inhibiteur des histones désacétylases, sur la carcinogenèse mammaire
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 conducted to determine if 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: 1) control diet (AIN-93G), 2) 0.1% SAHA (w/w), 3) 40% DER, or 4) 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 (H2ALys9, H2BLys5, and H4Lys5/8/12/16, but not H3Lys9 P < 0.001) and non-histone protein deacetylation (p53Lys373 and p53Lys382 P < 0.001), induced by DER, were reversed by SAHA. This indicates that DER's inhibition 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.