Research Progress on the Role of Epigenetic Methylation Modification in Hepatocellular Carcinoma

Figures & data

Table 1 Methylation-Related Biomarkers in HCC

Biomarker Gene	Methylation Type	Impacts and Mechanisms in HCC
RDH16	DNA methyltransferase inhibitor	HCC migration^Citation11
DLC1	DNA hypomethylation	Associated with satellite lesions and incomplete tumor capsule^Citation12
BAIAP2L2	DNA methylation	Potential prognosis and therapeutic target^Citation19
UBE2	DNA methylation	Diagnostic and prognostic^Citation20
RPS24	DNA methylation	Cell proliferation and immunosuppression^Citation20
STAP1	DNA methylation	Diagnostic and prognostic value of HBV-related hepatocellular carcinoma^Citation13
CCDC50	DNA hypomethylation	HCC prognosis^Citation20
CKS2	DNA abnormal methylation	Positive correlation with immunological markers^Citation15
FARSB	DNA hypomethylation	Immune infiltration^Citation16
m-SEPT9	DNA	Molecular targeted agents treatment efficacy^Citation21
WHSC1	DNA	Prognosis and therapeutic target^Citation22
TET1	Demethylation	Immune infiltration and carcinogenesis^Citation23
AC115619	M6A	Regulation of tumour progression and prognosis^Citation24
KAA1429	M6A	Sorafenib-resistant hepatocellular carcinoma and HCC tumour metastasis^Citation25
AURKA	lncRNAs M6A	Prognosis and treatment^Citation26
GBAP1	M6A	Prognosis indicator and therapeutic target^Citation27
LncRNA FAM111A-DT	M6A	Proliferation of HCC cells^Citation28
LncRNA LEAWBIH	M6A	Therapeutic target^Citation28
LncRNA H19	M5C	Diagnosis and treatment^Citation29
PRMT3	Histone methylation	Drug resistance^Citation30

Table 2 Effect of DNA Promoter Methylation Modification of Diverse Genes on HCC

Gene Site	Methylated Target Genes	Promoter Methylation Status	Influence on Self-Expression	Mechanisms on HCC
NC_000001. 11	PIGC	Hyper	Inhibit	An oncogene and its hypermethylation inhibits HCC development^Citation66
	CDH5	Hyper	Inhibit	Potential tumor suppressor genes, hypermethylation improve the occurrence and development of HCC^Citation67
	RAB42	Hypo	Promote	A potent prognostic biomarker for HCC^Citation68
	WASF2	Hypo	Promote	Hypomethylation boosts HCC proliferation, and WASF2 inactivation leads to tumor suppression in vitro^Citation52
	LINE-1	Hypo	Promote	Hypomethylation can inadvertently lead to the activation of various tumor promoting genes, it identified as an independent prognostic factor for overall survival and disease progression^Citation56,Citation69
NC_000003. 12	VIPR1	Hyper	Inhibit	VIPR1 transcriptional silencing caused by DNA methylation may contribute to the initiation and progression of HCC^Citation70
	MUC13	Hypo	Promote	Positive effect on the production of CSCs and promotes the carcinogenesis of liver cells^Citation55
	HDAC11	Hypo	Promote	Improving HCC progression, related to sorafenib chemotherapy resistance^Citation53
NC_000004. 12	SFRP2	Hyper	Inhibit	Significantly elevated in poorly differentiated HCC and is an independent risk factor for the development of HCC, it is expected to be used as a non-invasive diagnostic biomarker for HBV-HCC^Citation71
	CDKL2	Hyper	Inhibit	Hypermethylation status has high specificity and sensitivity for distinguishing adjacent paracancerous tissues from HCC tissues^Citation72
NC_000005. 10	APC	Hyper	Promote	APC inhibits tumor growth and reduces the proportion of microvascular invasion^Citation48
	VTRNA2-1	Hyper	Inhibit	The hypermethylation status of the promoter is strongly associated with tumor size, pathological vascular invasion, tumor recurrence, and more advanced tumor stage^Citation42
	CSF1R	Hypo	Independent of the level of expression	Related to tumor stage and degree of malignancy^Citation35
NC_000007. 14	STEAP4	Hyper	Inhibit	Inhibits the proliferation and metastasis of HCC cells and mediates the biological effects of HCC cells through the inhibition of the PI3K/AKT/mTOR pathway^Citation44
NC_000008. 11	ADRA1A	Hyper	Inhibit	Low expression promoter was significantly in connection with alcohol intake, AFP and cirrhosis, but not link to TNM stage^Citation73
NC_000009. 12	RECK	Hyper	Inhibit	Promoter hypermethylation is linked with HCV-HCC, and varying degrees of methylation are engaged with serum RECK levels, lymph node metastasis, and vascular infiltration^Citation49
	GLDC	Hypo	Promote	Promote the invasion and proliferation of liver cancer^Citation74
NC_000011. 10	ATM	Hyper	Inhibit	Encouraging HCC development, possibly increasing the risk of HCC by regulating ATM expression^Citation73
	KCNQ1	Hyper	Inhibit	Tumor suppressor factor, and its expression is reduced to inhibit liver cancer metastasis^Citation75
	CCND1	Hypo	Promote	Prospective diagnostic marker in patients with AFP-negative HBV-HCC and AFP-positive CHB^Citation57
NC_000012. 12	USP44	Hyper		Unmethylated in normal tissues, hypermethylated only in HCC tissues^Citation76
	NKG2D	Hyper	Inhibit	Has good predictive value for HCC diagnosis^Citation62
	PZP	Hyper	Inhibit	PZP significantly inhibits the proliferation, invasion and migration of HCC cells^Citation77
NC_000013. 11	PCDH17	Hyper	Inhibit	Regulate EMT and cell proliferation related proteins, influences the biological behavior of HCC and inhibits HCC Proliferation and progression^Citation60
	SPG20	Hyper		Hypermethylation status is significantly possessing intrahepatic metastasis and results in HCC metastasis^Citation72
NC_000016. 10	JPH3	Hyper		Tumor suppressors, affect the EMT of HCC cells^Citation51
	CDH13	Hyper	Inhibit	Tumor suppressor gene, methylation in HCC is significantly increased^Citation78
NC_000017. 11	Sox15	Hyper	Inhibit	Tumor suppressor genes, down regulation of Wnt pathway and its target gene suppression^Citation47
	TMEM106A	Hyper	Inhibit	Downward regulated predictions have a poor prognosis, and their levels distinguish between tumor and paracancerous tissues^Citation79
	SEPT9	Hyper	Promote	Predict MVI and tumor proliferation in HCC, and plasma mSEPT9 can be used as an excellent biomarker for HCC diagnosis and early detection in clinical settings^Citation80,Citation81
	RNF135	Hyper	Inhibit	Independent predictor of poor prognosis in patients with HCC^Citation82
NC_000020. 11	NAAT	Hyper		Phosphorylation of LKB3 and PTEN was altered to regulate the PI3K-Akt signaling pathway and promote HCC development^Citation17
	CTCFL	Hypo		Hypomethylation differs significantly from benign lesion samples, shortened survival, and increased vascular involvement^Citation54
NC_000023. 11	ZCCHC13	Hypo	Promote	Promotes G1-S transition and promotes cell cycle progression, associated with abnormal activation of ATK/ERK/c-MYC/CDK pathway^Citation58

Figure 1 HCC methylation occurs in DNA, RNA, and protein. M6A modifications are regulated by a family of methyltransferases (writer), demethylases (eraser), and specific RNA binding proteins(reader). The methyltransferase family includes METTL family and WTAP. Demethylases include FTO, ALKBH5 meanwhile others, which directly remove m6A modifications from mRNAs. Specific RNA binding proteins consist of YTH domain proteins, the IGF binding protein 2 family, eukaryotic initiation factor 3, and nuclear heterogeneous protein2β1.

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