Regulation of the INK4a/ARF locus by histone deacetylase inhibitors

Despite the importance of the INK4a/ARF locus in tumor suppression, its modulation by histone deacetylase inhibitors (HDACis) remains to be characterized. Here, we have shown that the levels of p16(INK4a) are decreased in human and murine fibroblasts upon exposure to relatively high concentrations of trichostatin A and sodium butyrate. Interestingly, the levels of p19(ARF) are strongly upregulated in murine cells even at low concentrations of HDACis. Using ARF-deficient cells, we have demonstrated that p19ARF plays an active role in HDACi-triggered cytostasis and the contribution of p19ARF to this arrest is of higher magnitude than that of the well established HDACi target p21(Waf1/Cip). Moreover, chemically induced fibrosarcomas in ARF-null mice are more resistant to the therapeutic effect of HDACis than similar tumors in wild type or p21(Waf1/Cip)-null mice. Together, our results have established the tumor suppressor ARF as a relevant target for HDACi chemotherapy.