Histone deacetylases (HDACs) play a crucial role in several physiological and pathological cell functions, including cell development and
cancer, by deacetylating both
histones and others
proteins. HDACs belong to a large family of
enzymes including Class I, II and IV as well as Class III or
sirtuins subfamilies, that undergo a complex transcriptional and post-translational regulation. In current years, antitumor
therapy is attempting to exploit several chemical classes of inhibitors that target HDACs, frequently reported to be misregulated in
cancer. Nevertheless, the identity of gene products directly involved in
tumorigenesis and preventing HDAC misregulation in
cancer is still poorly understood. Recent evidence has demonstrated that the
tumor suppressors HIC1 and DBC1 induce direct repression of
Sirt1 function, whereas Chfr and REN(KCTD11/KASH family) downregulate HDAC1, by inducing its
ubiquitin-dependent degradation. Loss of these gene products leads to imbalanced enhancement of HDAC activity and subsequently to
oncogenesis. All these genes are frequently deleted or silenced in human
cancers, highlighting the role of endogenous
HDAC inhibitors to counteracts HDAC-mediated
tumorigenesis. Thus, endogenous
HDAC inhibitors represent a promising class of "
antitumor agents" thanks to which
oncogenic addiction pathways may be selectively therapeutically targeted.