Epigenetics in hepatocellular carcinoma: An update and future therapy perspectives

Table 1 MicroRNAs in hepatocellular carcinoma and their characteristics

Role	miRNA	Characteristics	Ref.
Viral replication	miR-141	Represses HBV expression and replication	[48]
	miR-122	Inhibits HBV replication	[50]
	miR-122	HCV RNA stabilization, propagation and replication	[51]
	miR-1	Increases HBV replication	[56]
Tumor supressor	miR-138	Down-regulated in HCC tissues. miR-138 can directly target cyclin D3	[61]
	miR-26a and miR-26b	Down-regulated in tumors compared to paired non-tumor tissues	[64]
	miR-125b	Arrests cell cycle progression, and inhibits migration and invasion by directly targeting the oncogene LIN28B2	[65]
	miR-140-5p	Suppresses tumor growth and metastasis by targeting TGFBR1 and FGF9	[66]
	miR-122a	Mice lacking the gene encoding miR-122a are viable but develop temporally controlled steatohepatitis, fibrosis, and HCC	[68]
Target tumor initiating cells	miR-181	Maintains the stemness of liver cancer stem cells, target liver differentiation transcription factors CDX2 and GATA6	[78]
	miR-150	Overexpression led to reduction of CD133+ cells	[80]
	miR-548c-5p	Ectopic overexpression inhibited proliferation, migration, and invasion of CD90+ HepG2 cells by down-regulating the expressions of β-catenin, Bcl-2, Tg737, Bcl-XL, and caspase 3	[81]

HBV: Hepatitis B virus; HCV: Hepatitis C virus; HCC: Hepatocellular carcinoma; miRNAs: MicroRNAs.

Table 2 List of drugs targeting epigenetic modifications in hepatocellular carcinoma

Epigenetic modification	Targets	Drug(s)	Cell line/Animal model/Clinical trial phase	Results	Ref.
DNA methylation	DNA methyltransferase	Zebularine	Huh7 and KMCH cell linesHuman xenograft models	Zebularine-sensitive cell lines (Huh7 and KMCH) showed preferential demethylation of genes for tumor suppression, apoptosis, and cell cycle regulationIn vivo inhibition of tumor growth in xenograft model	[110]
	DNA methyltransferases	Zebularine	HepG2 cell line	Zebularine treatment inhibited cell proliferation and induced apoptosis in HepG2 cell line	[109]
	DNA methyltransferases	5-aza-2’-deoxycytidine	MMC-7721 and HepG2 cell lines	Inhibited telomerase activity, accompanied by reactivation of p16 and c-Myc. DAC synergized with cisplatin on growth inhibition	[111]
Histone acetylation	Histone deacetylase	Belinostat	PLC/PRF/5, Hep3B and HepG2 cell lines	Inhibited cell growth and induced apoptosis	[112]
	Histone deacetylase	Belinostat	Multi-center phase I/II clinical trial	Stabilized tumor in non-resectable advanced HCC	[115]
	Histone deacetylase	Suberoylanilide hydroxamic acid	HepG2, Hep3B and SK- Hep1 cell lines	Tumor necrosis factor-related apoptosis-inducing ligand-induced apoptosis	[114]
Combination	Histone deacetylase + tyrosine kinase-inhibitors	Panobinostat + sorafinib	Huh7, Hep3B and HepG2 cell lines HCC xenograft model	Induction of apoptosisCombined panobinostat and sorafenib decreased vessel density, tumor volume and increased survival in HCC xenografts	[124]

HCC: Hepatocellular carcinoma.