Pathological Role of HDAC8: Cancer and Beyond

Abstract

Histone deacetylase 8 (HDAC8) is a class I HDAC that catalyzes the deacetylation of histone and non-histone proteins. As one of the best-characterized isoforms, numerous studies have identified interacting partners of HDAC8 pertaining to diverse molecular mechanisms. Consequently, deregulation and overexpression of HDAC8 give rise to diseases. HDAC8 is especially involved in various aspects of cancer progression, such as cancer cell proliferation, metastasis, immune evasion, and drug resistance. HDAC8 is also associated with the development of non-cancer diseases such as Cornelia de Lange Syndrome (CdLS), infectious diseases, cardiovascular diseases, pulmonary diseases, and myopathy. Therefore, HDAC8 is an attractive therapeutic target and various HDAC8 selective inhibitors (HDAC8is) have been developed. Here, we address the pathological function of HDAC8 in cancer and other diseases, as well as illustrate several HDAC8is that have shown anti-cancer effects.

Keywords: HDAC8; HDAC8 selective inhibitors; cancer; epigenetics.

Figure 1

Crystal structure of HDAC8. (A) Head-to-head dimeric arrangement of HDAC8 (PDB ID: 2V5W [27]). Two monomers of HDAC8 are shown in light and dark yellow. Zinc and potassium are represented as grey and purple spheres, respectively (B) Liganded form of HDAC8 (PDB ID: 1T67 [15]). L2 loop and MS-344 are colored grey and green, respectively. (C) Catalytic machinery of HDAC8 (PDB ID: 1T64 [15]). Zinc ion is coordinated to three HDAC8 residues and two oxygen atoms of TSA. The zinc coordination shell is indicated by dashed lines. (D) Active site of HDAC8 (PDB ID: 1T64 [15]). Six key residues form the hydrophobic tunnel that occupies two TSA molecules.

Figure 2

Schematic representation of human HDAC8 and its regulation. HDAC8 is upregulated by transcription factors and downregulated by miRNA, autophagy, and proteasomal degradation.

Figure 3

Schematic representation of histone and non-histone substrates of HDAC8. HDAC8 deacetylates histones and suppresses transcription of target genes. HDAC8 also deacetylates non-histone substrates such as SMC3, α-tubulin, cortactin, HSP20, p53, PKM2, AKT, ERRα, and c-Jun.

Figure 4

Schematic representation of pathological functions of HDAC8 in cancer. HDAC8 promotes tumor growth by enhancing tumor cell proliferation and suppressing apoptosis. HDAC8 also enhances metastasis and is involved in drug resistance and immune evasion.