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.

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.

• Authors: Zongjian Zhu, Weiqin Jiang, John N McGinley, Henry J Thompson
• Journal: Cancer prevention research (Philadelphia, Pa.) (Cancer Prev Res (Phila)) Vol. 6 Issue 4 Pg. 290-8 (Apr 2013) ISSN: 1940-6215 [Electronic] United States
• PMID: 23365133 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Antineoplastic Agents
• Histone Deacetylase Inhibitors
• Hydroxamic Acids
• Vorinostat
• Methylnitrosourea
• Histone Deacetylases

Topics

• Animals
• Antineoplastic Agents (pharmacology, therapeutic use)
• Breast Neoplasms (chemically induced, diet therapy, prevention & control)
• Caloric Restriction
• Cell Transformation, Neoplastic
• Disease Models, Animal
• Female
• Histone Deacetylase Inhibitors (administration & dosage)
• Histone Deacetylases (metabolism)
• Hydroxamic Acids (administration & dosage)
• Methylnitrosourea
• Rats
• Rats, Sprague-Dawley
• Vorinostat