Multifaceted Influence of Histone Deacetylases on DNA Damage Repair: Implications for Hepatocellular Carcinoma

Abstract

Hepatocellular carcinoma (HCC) is one of the most commonly diagnosed cancers and a leading cause of cancer-related mortality worldwide, but its pathogenesis remains largely unknown. Nevertheless, genomic instability has been recognized as one of the facilitating characteristics of cancer hallmarks that expedites the acquisition of genetic diversity. Genomic instability is associated with a greater tendency to accumulate DNA damage and tumor-specific DNA repair defects, which gives rise to gene mutations and chromosomal damage and causes oncogenic transformation and tumor progression. Histone deacetylases (HDACs) have been shown to impair a variety of cellular processes of genome stability, including the regulation of DNA damage and repair, reactive oxygen species generation and elimination, and progression to mitosis. In this review, we provide an overview of the role of HDAC in the different aspects of DNA repair and genome instability in HCC as well as the current progress on the development of HDAC-specific inhibitors as new cancer therapies.

Keywords: DNA repair; Hepatocellular carcinoma; Histone deacetylases.

Fig. 1. Model of DDR.

DNA damage can be produced by reactive oxygen compounds arising through redox-cycling events involving environmental toxic agents, including tobacco products, chemical drugs, ultraviolet exposure, industrial exhaust pollution, etc. The presence of a lesion in the DNA can block genome replication and transcription. DSB sensors, such as ATM/ATR, CHK1/2 and γH2AX, can recognize chemically and physically derived DNA lesions and recruit various DNA repair factors to initiate DNA repair pathways. DSB, double strand break; ATM, ataxia-telangiectasia mutated; ATR, ataxia telangiectasia and Rad3-related protein; CHK1/2, checkpoint kinase 1/2.

Fig. 2. Overview of homologous recombination.

Schematic of DNA double-strand breaks (DSBs) and their repair by homologous recombination. CtIP and MRN bind to the 3′-overhang single-stranded DNA as initiators to regulate nucleases EXO1 and BLM/DNA2, which carry out further resection of DNA and recruit RPA. The recombinase RAD51 replaces phosphorylated RPA and interacts with BARD1, PALB2 and BRCA2, initiating the SDSA pathway or DSBR pathway to repair DNA. DSB, double strand break; CtIP, human C-terminal binding protein; MRN, constituted by MRE11, RAD50 and NBS1; EXO1, Exonuclease 1; BLM, Bloom; DNA2, DNA replication ATP-dependent helicase/nuclease 2; RPA, Replication Protein A; BARD1, BRCA1-associated RING domain 1; PALB2, Partner and Localizer of BRCA2; BRCA2, breast cancer 2; SDSA, synthesis-dependent strand annealing; DSBR, double-strand break repair.

Fig. 3. Overview of non-homologous end joining.

The Ku70–Ku80 heterodimer plus DNA-PK catalytic subunit (DNA-PKcs) recruited to a Ku/DNA-PKcs complex binds to DSBs and roles in phosphorylating Artemis and enabling it to cut the dissociative DNA end. Then, the complex improves their subsequent binding by the NHEJ polymerase, nuclease and ligase complexes (pol λ, pol µ, and TdT), which are involved in broken strand repair. XRCC4/XLF are recruited to stabilize the DNA end structure and fine-tune DNA end ligation. DNA-PK, DNA-dependent protein kinase; DNA-PKcs, DNA-dependent protein kinase catalytic subunit; DSB, double strand break; XRCC4, X-ray repair cross-complementing 4; NHEJ. nonhomologous end joining; XLF, XRCC4-like factor.

Fig. 4. Overview of alternative end jointing.

Alternative end jointing starts when Ku70 and Ku80 remain at low levels. As a sensor, PARP1 binds at the damage site. Then, CtIP phosphorylates MRN to generate 3′-overhangs. DNA pol θ extends the DNA ends, and DNA ligase I/III seals the stable annealing partner. PARP1, poly (ADP-ribose) polymerase 1; CtIP, human C-terminal binding protein; MRN, constituted by MRE11, RAD50 and NBS1.

Fig. 5. Overview of single-strand annealing.

Single-strand annealing starts when RAD51 and its mediators are disrupted. RAD52 substitutes RPA, generating redundant unannealed flaps, which are removed by the ERCC1/XPF nuclease. RPA, Replication Protein A; ERCC1, Excision repair cross-complementation 1 protein; XPF, Xeroderma pigmentosum complementation group F.

Fig. 6. Schematic diagram of the regulatory network of HDACs on DNA sensors and DNA repair factors.