Histone deacetylases (HDACs) function by decreasing the level of histone acetylation leading to changes in the chromatin structurethat primarily facilitates gene-specific repression of transcription. There are 18 HDACs, divided into four classes based on function and sequence similarity.
Class I HDACs comprise HDAC1, HDAC2, HDAC3 and HDAC8 and are noted to be ubiquitously expressed in all cells. HDAC1 plays a critical role in cell proliferation during embryogenesis and is responsible for upregulating cyclin-dependent kinase (CDK) inhibitors, p21 and p27; and HDAC2 appears to be critical to cardiac-specific cell development. Meanwhile, HDAC3 is implicated in early embryonic growth, and its inactivation has been observed to delay cell cycle progression, cell cycle-dependent DNA damage and unproductive repair, and apoptosis.
Class IIA HDACs consisting of HDAC4, HDAC5, HDAC7, and HDAC9 and seem to have tissue specific functions in the vascular and nervous systems, bone development, heart and skeletal muscle. Class IIB HDAC includes HDAC6, HDAC8, and HDAC10. HDAC6 has been identified as a tubulin-deacetylase while the functionality of HDAC8 and HDAC10 have not been established.
Class III is a family of NAD+-dependent proteins comprised of SIRT1-7, and are not be inhibited by trichostatin A (TSA) whereas Class I and II HDACs display sensitivity to TSA.
The Class IV HDAC contains only HDAC11, which is structurally similar to Class I and II HDACs, however, its relevant binding partners and target substrates remain unclear.
In addition to histones, HDACs also target non-histone proteins as substrates, including transcription factors such as p53, E2F1-3, c-Myc, YY1, NF-κB, GATA1-3, HIF-1α and CREB, indicating that HDACs regulate gene expression by a distinct mechanism separate from their effects on chromatin. [1]
Since HDACs are involved in a variety of critical intracellular pathways that impact cell-cycle progression and apoptosis, inhibition of HDAC activity presents a useful target in oncology to regulate chromatin conformation and transcriptional activity of tumor cells. Compared with non-malignant cells, certain HDAC family members are aberrantly expressed in cancer cells. As a consequence, a number of HDAC inhibitors such as SAHA (Vorinostat) and TSA have been developed to inhibit tumor growth by causing cell cycle arrest and apoptosis or inhibiting angiogenesis. In addition, a variety of HDAC inhibitors such as SAHA, PCI-24781, MS-275, FK228, Valproic acid, and Butyrate have been evaluated in clinical trials for their potential application as a monotherapy or in combination with other cytotoxins for the treatment of cancer. The pan-HDAC inhibitor SAHA and Class I specific Romidepsin have been approved by FDA for treatment of advanced and refractory cutaneous T cell lymphoma (CTCL). These compounds demonstrate that HDAC inhibitors can be well tolerated and exhibit significant activity against a variety of human malignancies, especially to hematological malignancies. [1]
