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.
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.
Cancer Prevention Laboratory, Colorado State University, 1173 Campus Delivery, Fort Collins, CO 80523, USA.
Zongjian
Z
Zhu
Weiqin
W
Jiang
John N
JN
McGinley
Henry J
HJ
Thompson
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D001943:Breast Neoplasms / Q000139:chemically induced / Q000178:diet therapy* / Q000517:prevention & control; D031204:Caloric Restriction; D002471:Cell Transformation, Neoplastic; D004195:Disease Models, Animal; D005260:Female; D056572:Histone Deacetylase Inhibitors / Q000008:administration & dosage*; D006655:Histone Deacetylases / Q000378:metabolism*; D006877:Hydroxamic Acids / Q000008:administration & dosage*; D008770:Methylnitrosourea; D051381:Rats; D017207:Rats, Sprague-Dawley; D000077337:Vorinostat
D000970:Antineoplastic Agents; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D000077337:Vorinostat; D008770:Methylnitrosourea; D006655:Histone Deacetylases