Histone Deacetylases and Cancer-Associated Angiogenesis: Current Understanding of the Biology and Clinical Perspectives

Histone deacetylase enzymes (HDACs) have been shown to be important to the development and progression of human cancers. Angiogenesis is a vital process that facilitates tumor growth and survival. More than a dozen of different activators and inhibitors are involved in at least as many diverse mechanisms to control angiogenesis. HDACs directly or indirectly control many of these regulators. In the current review, we give a brief overview of molecular mechanisms of HDAC actions and link these to the current knowledge concerning HDAC-mediated regulation of tumor-associated angiogenesis. HDAC specific knockdown studies and the use of pan-HDAC inhibitors (HDACi) contributed to the identification of: (i) HDACs that are key to angiogenesis and (ii) their multiple protein targets essential for angiogenic process. The clinical development of HDACi is an active area of investigation. In the scope of this review, we highlight several preclinical studies that examine the anti-angiogenic role of HDACi. Certainly, there is still much to be learned about the use of HDACi to inhibit tumoral angiogenesis. Recent efforts in the clinics aiming to combine broad HDACi (mainly vorinostat, which is FDA approved for T-cell lymphoma) with other anti-angiogenic therapies could, however, bring the proof that the lack of specificity of pan-HDACi may not be a major issue as compared with (long-time idealized) selective inhibitors targeting one particular HDAC.