New Insights into the Epigenetics of Hepatocellular Carcinoma

Abstract

Hepatocellular Carcinoma (HCC) is one of the most predominant malignancies with high fatality rate. This deadly cancer is rising at an alarming rate because it is quite resistant to radio- and chemotherapy. Different epigenetic mechanisms such as histone modifications, DNA methylation, chromatin remodeling, and expression of noncoding RNAs drive the cell proliferation, invasion, metastasis, initiation, progression, and development of HCC. These epigenetic alterations because of potential reversibility open way towards the development of biomarkers and therapeutics. The contribution of these epigenetic changes to HCC development has not been thoroughly explored yet. Further research on HCC epigenetics is necessary to better understand novel molecular-targeted HCC treatment and prevention. This review highlights latest research progress and current updates regarding epigenetics of HCC, biomarker discovery, and future preventive and therapeutic strategies to combat the increasing risk of HCC.

Figure 1

CpG methylation. (a) DNA methylation is catalyzed by three methyl transferase genes (DNMT1, DNMT3a, and DNMT3b) that add methyl group (CH₃) at 5th carbon position of pyrimidine ring of cytosine. S-adenosyl methionine (SAM-CH3) acts as a methyl donor. (b) Cytosine to cytosine sulfonate: sulfonation of cytosine causes C to T transition followed by deamination. Cytosine sulfonate to uracil sulfonate: conversion of cytosine sulfonate to uracil sulfonate leads to alkali desulfonation. Uracil sulfonate is converted into uracil. PCR distinguishes methylated CpG from unmethylated CpG because methylated cytosine resists this chemical treatment [124, 125].

Figure 2

Emerging signaling pathways in HCC: chromatin remodeling: restricting transcriptional and DNA condensation occurs as a result of histone deacetylation catalyzed by HDACs in nucleosome. In contrast, transcriptional activation also occurs using chromatin remodeling complexes by allowing access to transcription machinery via nucleosome restructuring. Notch signaling: NOTCH receptor is cleaved photolytically when protein ligand binds to its extracellular domain. This binding releases its intracellular domain (NOTCH-ICD) that enters into nucleus to modify target gene expression (such as SOX9, HEY, and HES). Hedgehog (Hh) signaling: nuclear translocation of the transcription factor (TF) GLI occurs as a result of PTCH inhibitory effect on SMO and this event takes place in the presence of Hh signaling. Hippo signaling: kinase complexes Lats1/2-Mob1 and MST1/2-SVA1 are activated with phosphorylation of the transcription factor YAP resulting in prevention of its nuclear translocation. This event involves the use of upstream regulators of hippo pathway (i.e., FDM6, NF2, and FAT). Microbiota and lymphotoxins: NF-kβ signaling activates and produces proinflammatory molecules such as TNF-α and cytokines due to recognition of microbial ligands (LPS/PAMPs) by TLKRs (e.g., TLK4) on the hepatic stellate cells [126].

Figure 3

Role of miRNA, mRNA, and lncRNA in regulation of apoptosis, migration, metastasis, tumorigenicity, cell cycle, invasion, and cell proliferation. PCNA (Proliferating Cell Nuclear Antigen) regulation is related to PCNA-AS1 effects and this event involves the formation of RNA hybridization that increases PCNA mRNA stability. (b) H19 affects let-7 mediated genes involved in promotion of metastasis specifically IGF2BP1 (insulin-like growth factor 2 mRNA-binding protein). (c) Autophagy genes, for example, p62, ATG7 (autophagy-related gene 7), and ULK1 (unccoordinated-51- (unc-51-) like kinase 1), are regulated by PTENP1 that is targeted by miR-17 family. (d) The stability of IL-11 (interleukin-11) mRNA is increased by lncRNA-ATB. (e) miR-125b negatively targeted by HOTTIP. (f) The regulation of MALAT1 is regulated in the nucleus after being binded with miR-9 following AGO2-dependent path. (g) The activity and expression of miR-372 are repressed after getting binded with HULC. Target mRNA of miR-372, that is, Prkacb (cAMP-dependent protein kinase catalytic subunit beta), level is increased in response to mi-372 reduction [127].