DNA and histone methylation in gastric carcinogenesis

Table 1 Methylation machinery in gastric cancer

Gene	Function	Alteration in cancer	Ref.
DNMT1	Maintenance of methylation Repression of transcription	Upregulation Mutation	Kanai et al[93] Fang et al[94] Ding et al[95] Yang et al[96] Mutze et al[97]
DNMT3A	De novo methylation during embryogenesis Imprint establishment Repression	Upregulation Mutation	Ding et al[95] Fan et al[98] Yang et al[96]
DNMT3B	De novo methylation during embryogenesis Repeat methylation Repression	Upregulation Mutation	Ding et al[95] Su et al[99] Hu et al[100] Yang et al[96]
MeCP2	Transcription repression	Upregulation Mutation	Wada et al[101]
MBD1	Transcription repression	Upregulation Mutation	-
MBD2	Transcription repression DNA demethylase	Downregulation Mutation	Kanai et al[102]
MBD3	Transcription repression, but requires MBD2 to recruit it to methylated DNA	Upregulation Mutation	-
MBD4	Transcription repression DNA repair Glycosylase domain, repair of deaminated 5-methyl C	Downregulation Mutation	Pinto et al[38] D'Errico et al[37]
Kaiso	Transcription repression	Upregulation	Ogden et al[103]
G9a	Histone methyltransferase	Gene Repression	Lee et al[104]
RIZ1	Histone methyltransferase	Underexpression	Oshimo et al[105]
PRDM2		Mutation	Pan et al[106]
SUZ12	Histone methyltransferase	Upregulation	Yoo et al[107]
BMI1	Histone methyltransferase	Upreguletion	Liu et al[108] Xiao et al[109] Lu et al[110] Zhang et al[111] Li et al[112]
EVI1	Histone methyltransferase	Chromosomal rearrangement	Takahata et al[113]
EZH2	Histone methyltransferase	Amplification Upregulation Mutation	Mattioli et al[114] Varambally et al[115] Fujii et al[48] Cai et al[47] Choi et al[46] Zhou et al[116]
NSD2/MMMSET	Histone methyltransferase	Upregulation Translocation	Hudlebusch et al[117]
SUV39H1 -2	Histone methyltransferase	Polymorphism	Li et al[84]
LSD1/BHC110	Histone demethylase	Downregulation	Magerl et al[118]
JARID1A-D	Histone demethylase	Upregulation Inactivation	Zeng et al[51]
JMJD2A	Histone demethylase	Mutation Upregulation	Li et al[119]
JHDM3A
JMJD1A-C	Histone demethylase	Downregulation	Katoh et al[120]

DNMT: DNA methyltransferase; EVH1: Domain containing 1; EZH2: Enhancer of zest homolog2; JARID: Jumonji, AT-rich interactive-domain; JHDM: JmjC domain-containing histone demethylase 1; JMJD: Jumonji domain containing 2; LSD1: Lysine specific demethylase; MBD: Methyl-CpG-binding domain; NSD2: Nuclear receptor-binding SET-domain protein 2; PRMT: Protein arginine methyltransferase 1; RIZ1: Retinoblastoma protein-interacting zinc finger 1; SUV39H: Suppressor of variation 3-9 homolog.

Table 2 Aberrant DNA methylation in gastric cancer

Gene	Role	Aberrant methylation	Ref.
ABCB1	Multidrug resistance	Hyper	Poplawski et al[121], Tahara et al[122], Lee et al[123]
ADAM23	Tissue cell invasion and metastasis	Hyper	Takada et al[124], Watanabe et al[125], Kim et al[126]
ALDH2	Oxidative pathway of alcohol metabolism	Hypo	Balassiano et al[127]
APC	Tissue cell invasion and metastasis Signal transduction	Hyper	Bernal et al[128], Ksiaa et al[63], Shin et al[69], Geddert et al[129]
ARPC1B (p41ARC)	Cell morphology	Hyper	Maekita et al[130], Shin et al[69]
BNIP3	Apoptosis	Hyper	Murai et al[131], Hiraki et al[132], Sugita et al[133]
BRCA1	DNA repair	Hyper	Bernal et al[128], Ryan et al[134]
CAV1	Tissue cell invasion and metastasis	Hyper	Yamashida et al[135]
CDH1	Tissue invasion and metastasis	Hyper	Leal et al[136], Bernal et al[136], Borges et al[61], Tahara et al[122], Al-Moundhri et al[137], Balassiano et al[127]
CHFR	Cell cycle regulation	Hyper	Oki et al[138], Hiraki et al[139], Hu et al[140]
DAPK	Apoptosis	Hyper	Bernal et al[128], Zou et al[74], Hu et al[140], Tahara et al[122], Sugita et al[133]
FHIT	Apoptosis	Hyper	Leal et al[136], Bernal et al[128]
FLNC	Cell morphology	Hyper	Kim et al[126], Shi et al[141]
GATA4/5	Transcriptional factor	Hyper	Akiyama et al[142], Wen et al[143],
HAND1	Cell differentiation	Hyper	Maekita et al[130], Shin et al[69], Shi et al[141]
HRAS	Signal transduction	Hypo	Fang et al[144], Luo et al[145]
IGFBP3	Cell cycle regulation	Hyper	Gigek et al[146], Ryan et al[134], Chen et al[147]
LOX	Tissue cell invasion and adhesion	Hyper	Maekita et al[130], Shin et al[69], Tamura et al[148]
MGMT	DNA repair	Hyper	Bernal et al[128], Hibi et al[149], Ksiaa et al[63]; Zou et al[74], Schneider et al[14], Hiraki et al[139], Balassiano et al[127], Shi et al[141]
MLF1	Cell differentiation	Hyper	Watanabe et al[125], Shi et al[141], Yamashita et al[135]
MLH1	DNA repair	Hyper	Bernal et al[128], Poplawski et al[121], Hiraki et al[139], Kim et al[150], Shin et al[58]
MOS	Cell cycle regulation	Hypo	Shin et al[58]
MTHFR	DNA synthesis DNA repair DNA methylation	Hypo	Balassiano et al[127]
MYC	Cell cycle regulation	Hypo	Fang et al[144], Luo et al[145]
P14ARF	Cell cycle regulation Apoptosis Cell differentiation	Hyper	Balassiano et al[127], Geddert et al[129]
P16	Cell cycle regulation	Hyper	Ksiaa et al[63], Dong et al[151], Zou et al[74], Shin et al[69], Hu et al[140], Ryan et al[134], Geddert et al[129], Balassiano et al[124], Al-Moundhri et al[137], Shin et al[58]
PRDM5	Cell differentiation	Hyper	Watanabe et al[125], Shu et al[152]
RAR-beta 2	DNA binding Activation transcription	Hyper	Bernal et al[128], Ksiaa et al[63]
RASSF1A/ RASSF2	DNA repair Cell cycle regulation	Hyper	Zou et al[74], Guo et al[153], Shin et al[58]
RORA	Cell differentiation	Hyper	Watanabe et al[125], Yamashida et al[131]
RPRM	Cell cycle regulation	Hyper	Bernal et al[128], Schneider et al[14]
RUNX3	Signal transduction	Hyper	Bernal et al[128], Sakakura et al[154], Lee et al[104], Zou et al[74], Hiraki et al[139], Tamura et al[148], Hu et al[140], Fan et al[155], Al-Moundhri et al[137]
SHP1	Signal transduction	Hyper	Bernal et al[128], Ksiaa et al[63],
TERT	Cell senescence	Hyper	Kang et al[67], Wang et al[75], Gigek et al[77]
TFF1	Repair gene	Hyper	Carvalho et al[156], Ryan et al[134]
THBD	Inflammation response	Hyper	Maekita et al[130]; Shin et al[69]
TWIST1	Cell differentiation	Hyper	Kang et al[67], Schneider et al[14]

ABCB1: ATP-binding cassette, sub-family B (MDR/TAP), member 1; ADAM23: ADAM metallopeptidase domain 23; ALDH2: Aldehyde dehydrogenase 2 family (mitochondrial); APC: Adenomatous polyposis coli; ARPC1B (p41ARC): Actin related protein 2/3 complex, subunit 1B, 41kDa; BNIP3: Adenovirus E1B 19kDa interacting protein 3; BRCA1: Breast cancer 1 gene; CAV1: Caviolin 1; CDH1: Cadherin 1; CHFR: Checkpoint with forkhead and ring finger domains; DAPK: Dapk death associated protein kinase; FHIT: Fragile histidine triad gene; FLNC: Filamin C, gamma; GATA4/5: GATA binding protein 4/5; GSTP1: Glutathione S-transferase pi 1; HAND1: Heart and neural crest derivatives expressed 1; HRAS: v-Ha-ras Harvey rat sarcoma viral oncogene homolog; IGFBP3: Insulin-like growth factor; binding protein 3; LOX: Lysyl oxidase; MGMT: O-6-methylguanine-DNA methyltransferase; MLF1: Myeloid leukemia factor 1; MLH1: MutL homolog 1; MOS: Moloney murine sarcoma viral oncogene homolog; MTHFR: Methylenetetrahydrofolate reductase (NADPH); MYC: v-myc myelocytomatosis viral oncogene homolog (avian); P14ARF: Cyclin-dependent kinase inhibitor 2A; P16: Cyclin-dependent kinase inhibitor 2A; PRDM5: PR domain containing 5; RAR-beta 2: Retinoic acid receptor β 2 gene; RASSF1A/RASSF2: Ras association (RalGDS/AF-6) domain family member 1/member 2; RORA: RAR-related orphan receptor A; RPRM: TP53 dependent G₂ arrest mediator candidate; RUNX3: Runt-related transcription factor 3; SHP1: Hematopoietic cell-specific protein-tyrosine phosphatase; TERT: Telomerase reverse transcriptase; TFF1: Trefoil factor 1; TFPI2: Tissue factor pathway inhibitor 2; THBD: Thrombomodulin; TWIST1: Twist homolog 1.