Mechanisms of selective anticancer action of histone deacetylase inhibitors

Histone deacetylases (HDACs) regulate transcription and specific functions, such as tumor suppression by p53, and are frequently altered in cancer. Inhibitors of HDACs (HDACI) possess anti-tumor activity and are well tolerated, suggesting that they might develop into a specific strategy for cancer treatment. Indeed, HDACIs have successfully entered clinical trials, but the molecular basis for their selective anti-tumor activities is not clear. Recent work on leukemias expressing the PML-RAR or AML1-ETO oncogenes, known to initiate leukemogenesis through deregulation of HDACs, shows that HDACIs induce massive blast-cell apoptosis. Interestingly, the pro-apoptotic activity of the drug is not due to the relief of oncogene-mediated inhibition of the p53 tumor-suppressor pathway but, instead, relies on the selective upregulation of the death receptors DR5 and Fas and their cognate ligands TRAIL and FasL. Significantly, normal myeloid progenitors are not sensitive to HDACI-induced apoptosis and oncogene expression is not sufficient to confer HDACI-sensitivity to normal cells, demonstrating that sensitivity to HDACI is a property of the fully transformed phenotype. In principle, our findings could thus apply to other cancers, where the contribution of HDACs to tumorigenesis is not yet defined.