Modified type

ONCO TSG 实验已证明 实验未证明 summary 与预后相关
ONCO TSG 实验已证明 实验未证明 summary 与预后相关
LncRNA-ME LncRNA-HM LncRNA-TF LncRNA LncRNA-RM L-M-H-T

Gene:CAV2

Type:proto-oncogene
Introduction:Hypermethylation of CGI silences the CAV2 gene, which can be used as a biomarker for breast cancer. Indeed, CAV2 is the gene encoding caveolin 2, which is involved in essential cellular functions, including signal transduction, lipid metabolism, control of cell growth and apoptosis, and it may have tumor suppressive effects. In all types of lung cancer, CAV2 is dysregulated at the RNA and protein levels. Experiments have confirmed that CAV2 gene transcription is downregulated in mice and humans with obstructive bladder disease. It was confirmed that the mRNA levels of CAV2 were significantly downregulated in human breast cancer tissues compared to the corresponding normal tissues.

Gene:CFL2

Type:proto-oncogene
Introduction:

Gene:FXYD1

Type:proto-oncogene
Introduction:

Gene:GNG11

Type:proto-oncogene
Introduction:

Gene:GSN

Type:proto-oncogene
Introduction:GSN expression is down-regulated in gastric cancer cell lines and promoter DNA methylation is involved in this process.GSN is an actin-binding protein, a key regulator of actin filament assembly and disassembly, involved in cell motility, shape and metabolism. Studies have shown that GSN gene transcription is down-regulated in breast cancer in humans and some animals, and that GSN activation may be a protective factor in treating cancer cells and fighting cancer. high expression of GSN inhibits invasion and migration of colon cancer cells. Some studies have also reported that GSN expression is higher in bladder cancer than in normal tissues, and patients with bladder cancer with upregulated GSN gene expression have a poorer prognosis. GSN is overexpressed in hepatocellular carcinoma (HCC) tissues, and high GSN expression is significantly associated with Edmondson pathological grading, envelope and multiple tumors. It has been proposed that GSN functions as both an oncogene and an oncogene repressor.

Gene:LEP

Type:proto-oncogene
Introduction:

Gene:MGLL

Type:proto-oncogene
Introduction:

Gene:MYLK

Type:proto-oncogene
Introduction:

Gene:SEMA3G

Type:proto-oncogene
Introduction:

Gene:SORBS1

Type:proto-oncogene
Introduction:

Gene:PDE2A

Type:proto-oncogene
Introduction:

Gene:ERBB2

Type:proto-oncogene
Introduction:ERBB2 is a member of the epidermal growth factor receptor family. It has been shown that ERBB2 is overexpressed in breast cancer and could be a promising therapeutic agent for breast cancer. overexpression of ERBB2 in breast cancer may be associated with hypomethylation of the CpG site in the enhancer region. Due to the reversible nature of DNA methylation, it may be possible to normalize gene expression by altering the DNA methylation level of ERBB2 in enhancers, which may have a therapeutic effect on breast cancer patients.

Gene:ESR1

Type:proto-oncogene
Introduction:ESR1 (estrogen receptor 1) is the gene that encodes the ER (estrogen receptor), which is expressed in approximately 70% of breast cancers. It has been shown that ESR1 can be used as a useful biomarker to predict the subsequent development of breast cancer.

Information on hub gene associated with BRCA and their corresponding CpG methylation sites.

✦"hyper" is hypermethylation,"hypo" is hypomethylation.
✦"+" for upregulated expression of the corresponding gene,"-" for the corresponding gene down-regulated expression.
Gene CPG site Chr Location Resign Relationship
CAV2 cg12739419
cg16260298
cg25274503 		chr7
chr7
chr7 		116500539
116500288
116500074 		promoter, 1st intron, S_shore
promoter, 1st intron, CGI
Promoter, 1st intron, CGI 		hyper(-)
hyper(-)
hyper(-)
CFL2 cg25027125 chr14 34713595 3rd intron, N_shore hyper(-)
FXYD1 cg03078169
cg05247914
cg07780528
cg17540545
cg18503912
cg22783327 		chr19
chr19
chr19
chr19
chr19
chr19 		35138887
35138797
35139430
35139451
35139375
35142354 		promoter, N_shelf, N_shore
promoter, N_shelf
promoter, N_shelf
promoter, N_shelf, N_shore
promoter, N_shelf, N_shore
5th intron, N_shore 		hyper(-)
hyper(-)
hyper(-)
hyper(-)
hyper(-)
Hypo(-)
GNG11 cg08038054 chr7 93921469 promoter hyper(-)
GSN cg13569051
cg13828579
cg14399183 		chr9
chr9
chr9 		121289425
121306136
121286030 		5′UTR, 10th intron
12th intron
5′UTR, 10th intron 		hyper(-)
hyper(-)
hyper(-)
LEP cg00840332
cg07464571
cg12782180
cg13381984
cg19594666
cg26814075 		chr7
chr7
chr7
chr7
chr7
chr7 		128241216
128240948
128240879
128241291
128241227
128241245 		promoter, CGI
promoter, CGI
promoter, CGI
promoter, 5′UTR, 1st exon, CGI
Promoter, CGI
Promoter, CGI 		hyper(-)
hyper(-)
hyper(-)
hyper(-)
hyper(-)
hyper(-)
MGLL cg18274619 chr3 127776009 enhancer, 4th intron hyper(-)
MYLK cg00465319
cg18731398 		chr3
chr3 		123620721
123695886 		3rd intron
16th intron 		hyper(-)
hyper(-)
SEMA3G cg11137980 chr3 52435210 5′UTR, 1st exon hyper(-)
SORBS1 cg02370232
cg06282596 		chr10
chr10 		95415608
95415722 		18th intron
18th intron 		hyper(-)
hyper(-)
PDE2A cg16640865 chr11 72590514 24th exon, CGI Hypo(-)
ERBB2 cg24657085
cg00459816
37860344
37862113 		enhancer
enhancer 		Hypo(+)
Hypo(+)
ESR1 cg22157087
cg17741339
cg18132851
cg23009221
cg07455133
152012887
152085619
152085641
152128588
152379044 		enhancer
enhancer
enhancer
enhancer
enhancer 		Hypo(+)
Hypo(+)
Hypo(+)
Hypo(+)
Hypo(+)

Gene:CEBPA

Type:tumor suppressor gene
Introduction:CEBPA (CCAAT/enhancer binding protein alpha) is an important transcription factor that is dysregulated in breast cancer and can promote indefinite tumor cell proliferation. Studies have demonstrated that hypermethylation of CpG islands in breast cancer is associated with dysregulation of CEBPA expression, and altering the methylation status of CpG islands in CEBPA may inhibit indefinite multiplication of breast tumor cells.

Gene:FBLN2

Type:tumor suppressor gene
Introduction:FBLN2 is a breast cancer oncogene used to encode an extracellular matrix protein that binds to calcium and a variety of extracellular ligands. Studies have shown that FBLN2 is down-regulated and frequently methylated in breast cancer and that hypermethylation of certain CpG island sites may be a major cause of FBLN2 expression down-regulation in breast cancer.

Gene:FAT4

Type:tumor suppressor gene
Introduction:FAT4 (FAT tumor suppressor homologue 4) is associated with the development of breast cancer and has tumor suppressive effects, inhibiting cell proliferation, invasion and metastasis. Studies have shown that FAT4 expression is repressed in breast cancer, i.e., reducing FAT4 expression causes tumorigenesis (experimental demonstration). Some findings showed that hypermethylation of FAT4 in CpG islands in breast cancer tissues was associated with the downregulation of its expression. It suggests that hypermethylation of FAT4 at CpG islands may promote tumor cell proliferation and thus tumor progression. The GO biology of FAT4 is the skeletal development.

Information on hub gene associated with BRCA and their corresponding CpG methylation sites.

✦"hyper" is hypermethylation,"hypo" is hypomethylation.
✦"+" for upregulated expression of the corresponding gene,"-" for the corresponding gene down-regulated expression.
Gene CPG site Chr Location Resign Relationship
CEBPA cg01437571
cg10099799
cg06621373
cg02493939


33792148
33794556
33794690
33794746 		Island
Island
Island
Island 		hyper(-)
hyper(-)
hyper(-)
hyper(-)
FBLN2 cg19392656
cg16604516
cg17561417
cg18603228
cg01896761
cg18406197
cg12700904
cg00201234






13590415
13590419
13590432
13590439
13590444
13590450
13590720
13590968 		Island
Island
Island
Island
Island
Island
Island
Island 		hyper(-)
hyper(-)
hyper(-)
hyper(-)
hyper(-)
hyper(-)
hyper(-)
hyper(-)
FAT4 cg12828819
cg04459504
cg05118638
cg10731073
cg08644023
cg03527919
cg15795630
cg03404279
cg22911422
cg12058185
cg23901852
cg17265829
cg08575049
cg04373334












12623686
12623735
12623731
12623733
12623741
12623744
12623753
12623757
12623796
12623827
12623834
12623842
12623888
12623899 		Island
Island
Island
Island
Island
Island
Island
Island
Island
Island
Island
Island
Island
Island 		hyper(-)
hyper(-)
hyper(-)
hyper(-)
hyper(-)
hyper(-)
hyper(-)
hyper(-)
hyper(-)
hyper(-)
hyper(-)
hyper(-)
hyper(-)
hyper(-)

Information on hub gene associated with BRCA and their corresponding CpG methylation sites.

✦"hyper" is hypermethylation,"hypo" is hypomethylation.
✦"+" for upregulated expression of the corresponding gene,"-" for the corresponding gene down-regulated expression.

Gene CPG site Chr Location Resign Relationship
CAV2 cg12739419
cg16260298
cg25274503 		chr7
chr7
chr7 		116500539
116500288
116500074 		promoter, 1st intron, S_shore
promoter, 1st intron, CGI
Promoter, 1st intron, CGI 		hyper(-)
hyper(-)
hyper(-)
CFL2 cg25027125 chr14 34713595 3rd intron, N_shore hyper(-)
GSN cg13569051
cg13828579
cg14399183 		chr9
chr9
chr9 		121289425
121306136
121286030 		5′UTR, 10th intron
12th intron
5′UTR, 10th intron 		hyper(-)
hyper(-)
hyper(-)
LEP cg00840332
cg07464571
cg12782180
cg13381984
cg19594666
cg26814075 		chr7
chr7
chr7
chr7
chr7
chr7 		128241216
128240948
128240879
128241291
128241227
128241245 		promoter, CGI
promoter, CGI
promoter, CGI
promoter, 5′UTR, 1st exon, CGI
Promoter, CGI
Promoter, CGI 		hyper(-)
hyper(-)
hyper(-)
hyper(-)
hyper(-)
hyper(-)
MYLK cg00465319
cg18731398 		chr3
chr3 		123620721
123695886 		3rd intron
16th intron 		hyper(-)
hyper(-)
SORBS1 cg02370232
cg06282596 		chr10
chr10 		95415608
95415722 		18th intron
18th intron 		hyper(-)
hyper(-)
ERBB2 cg24657085
cg00459816
37860344
37862113 		enhancer
enhancer 		Hypo(+)
Hypo(+)
ESR1 cg22157087
cg17741339
cg18132851
cg23009221
cg07455133
152012887
152085619
152085641
152128588
152379044 		enhancer
enhancer
enhancer
enhancer
enhancer 		Hypo(+)
Hypo(+)
Hypo(+)
Hypo(+)
Hypo(+)

Information on hub gene associated with BRCA and their corresponding CpG methylation sites.

✦"hyper" is hypermethylation,"hypo" is hypomethylation.
✦"+" for upregulated expression of the corresponding gene,"-" for the corresponding gene down-regulated expression.

Gene CPG site Chr Location Resign Relationship
CEBPA cg01437571
cg10099799
cg06621373
cg02493939


33792148
33794556
33794690
33794746 		Island
Island
Island
Island 		hyper(-)
hyper(-)
hyper(-)
hyper(-)
FBLN2 cg19392656
cg16604516
cg17561417
cg18603228
cg01896761
cg18406197
cg12700904
cg00201234






13590415
13590419
13590432
13590439
13590444
13590450
13590720
13590968 		Island
Island
Island
Island
Island
Island
Island
Island 		hyper(-)
hyper(-)
hyper(-)
hyper(-)
hyper(-)
hyper(-)
hyper(-)
hyper(-)
FAT4 cg12828819
cg04459504
cg05118638
cg10731073
cg08644023
cg03527919
cg15795630
cg03404279
cg22911422
cg12058185
cg23901852
cg17265829
cg08575049
cg04373334












12623686
12623735
12623731
12623733
12623741
12623744
12623753
12623757
12623796
12623827
12623834
12623842
12623888
12623899 		Island
Island
Island
Island
Island
Island
Island
Island
Island
Island
Island
Island
Island
Island 		hyper(-)
hyper(-)
hyper(-)
hyper(-)
hyper(-)
hyper(-)
hyper(-)
hyper(-)
hyper(-)
hyper(-)
hyper(-)
hyper(-)
hyper(-)
hyper(-)

Information on hub gene associated with BRCA and their corresponding CpG methylation sites.

✦"hyper" is hypermethylation,"hypo" is hypomethylation.
✦"+" for upregulated expression of the corresponding gene,"-" for the corresponding gene down-regulated expression.
Gene CPG site Chr Location Resign Relationship
FXYD1 cg03078169
cg05247914
cg07780528
cg17540545
cg18503912
cg22783327 		chr19
chr19
chr19
chr19
chr19
chr19 		35138887
35138797
35139430
35139451
35139375
35142354 		promoter, N_shelf, N_shore
promoter, N_shelf
promoter, N_shelf
promoter, N_shelf, N_shore
promoter, N_shelf, N_shore
5th intron, N_shore 		hyper(-)
hyper(-)
hyper(-)
hyper(-)
hyper(-)
Hypo(-)
GNG11 cg08038054 chr7 93921469 promoter hyper(-)
MGLL cg18274619 chr3 127776009 enhancer, 4th intron hyper(-)
SEMA3G cg11137980 chr3 52435210 5′UTR, 1st exon hyper(-)
PDE2A cg16640865 chr11 72590514 24th exon, CGI Hypo(-)

By analyzing breast cancer, paracancerous tissue, breast tumor and normal samples, the following conclusions were obtained：

  • ➤ Hypomethylation of the gene body region was associated with upregulation of gene expression and contributed to enhanced or activated gene expression in cancer tissues. Hypermethylation of the TSS1500, 5'UTR , and first exon regions was associated with gene down-regulation and resulted in diminished gene expression in breast cancer tissues.
  • ➤ The 3'UTR is overall biased towards hypermethylation. Enhancers tend to be hypermethylated,and enhancer hypermethylation is associated with upregulation of breast cancer gene expression and increased expression of breast carcinogenesis oncogenes.
  • ➤ CGI is predominantly hyper-methylated, while shores and shelves are more likely to be hypomethylated. Hypermethylation differences in the CGI region are associated with downregulation of gene expression, and hypomethylation in the shores region is associated with upregulation of gene expression. The DNA methylation distribution in both shores regions was scattered, while the DNA methylation distribution in CpG islands was more concentrated.CGI hypermethylation of promoters suppresses gene expression.
  • ➤ The cg14399183 and cg13569051 probes located in intron 10 of the GSN gene are protective factors against breast cancer, while the cg25274503 probe located in the first intron of the CAV2 gene is a risk factor for breast cancer.
  • ➤ PLK1 was an oncogene. In contrast, the high expression of the 17 genes (EGFR (211550_at), ACVR2A (205327_s_at), C AV 1 (203065_s_at), FAT4 (219427_at), ID1 (208937_s_at), ID4 (209292_at), KIT (205051_s_at), LEPR (207255_ at), MET (213816_s_at), NRG1 (208241_at), PPARG (208510_s_at), PRDM16 (220928_s_at), PREX2 (220732_at), PROX1 (207401_at), RYR3 (206306_at), SOX17 (219993_at), and STAT5A (203010_at)) could significantly improve the prognosis of breast cancer patients. However, the high expression of LEP (207092_ at) and VIM (201426_s_at) were weakly correlated with a good prognosis.
The effect of changes in expression levels of the 20 key genes on overall survival.

Gene:CAV2

Type:proto-oncogene
Introduction:Hypermethylation of CGI silences the CAV2 gene, which can be used as a biomarker for breast cancer. Indeed, CAV2 is the gene encoding caveolin 2, which is involved in essential cellular functions, including signal transduction, lipid metabolism, control of cell growth and apoptosis, and it may have tumor suppressive effects. In all types of lung cancer, CAV2 is dysregulated at the RNA and protein levels. Experiments have confirmed that CAV2 gene transcription is downregulated in mice and humans with obstructive bladder disease. It was confirmed that the mRNA levels of CAV2 were significantly downregulated in human breast cancer tissues compared to the corresponding normal tissues.

Gene:GSN

Type:proto-oncogene
Introduction:GSN expression is down-regulated in gastric cancer cell lines and promoter DNA methylation is involved in this process.GSN is an actin-binding protein, a key regulator of actin filament assembly and disassembly, involved in cell motility, shape and metabolism. Studies have shown that GSN gene transcription is down-regulated in breast cancer in humans and some animals, and that GSN activation may be a protective factor in treating cancer cells and fighting cancer. high expression of GSN inhibits invasion and migration of colon cancer cells. Some studies have also reported that GSN expression is higher in bladder cancer than in normal tissues, and patients with bladder cancer with upregulated GSN gene expression have a poorer prognosis. GSN is overexpressed in hepatocellular carcinoma (HCC) tissues, and high GSN expression is significantly associated with Edmondson pathological grading, envelope and multiple tumors. It has been proposed that GSN functions as both an oncogene and an oncogene repressor.

Key genes that are significantly correlated with prognosis.

✦"hyper" is hypermethylation,"hypo" is hypomethylation.
✦"+" for upregulated expression of the corresponding gene,"-" for the corresponding gene down-regulated expression.

Gene CPG site Chr Location Resign Relationship
CAV2 cg25274503 chr7 116500074 promoter, 1st intron, CGI hyper(-)
GSN cg13569051
cg14399183 		chr9
chr9 		121289425
121286030 		5′UTR, 10th intron
5′UTR, 10th intron 		hyper(-)
hyper(-)

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Gene:TPD52

Type:proto-oncogene
Introduction:

Proto-oncogenes and important distribution regions of histone modification signals that related to BRCA.

✦ "Up" for high degree of histone modification,"Down" for low degree of histone modification.
✦ "HM" for Histone Modification.
✦"+" for upregulated expression of the corresponding gene,"-" for the corresponding gene down-regulated expression.
✦In the graph of "Distribution", blue is the distribution of histone modifications in HMEC cells and red is the distribution of histone modifications in MCF-7 cells
Gene HM Distribution Location Relationship
TPD52 H3K36me3 (-400, 1400) Promoter Up(+)
H3K79me2 (400, 1200) Promoter Up(+)
H3K27ac chr8 (80989405,80996173bp)(81014221,81017206bp) super enhancer Up(+)
H3K9ac chr8 (80989405,80996173bp)(81014221,81017206bp) super enhancer Up(+)

Gene:NRG1

Type:tumor suppressor gene
Introduction:

Gene:GADD45A

Type:tumor suppressor gene
Introduction:

Tumor suppressor genes and important distribution regions of histone modification signals that related to BRCA.

✦ "Up" for high degree of histone modification,"Down" for low degree of histone modification.
✦ "HM" for Histone Modification.
✦"+" for upregulated expression of the corresponding gene,"-" for the corresponding gene down-regulated expression.
✦In the graph of "Distribution", blue is the distribution of histone modifications in HMEC cells and red is the distribution of histone modifications in MCF-7 cells
Gene HM Distribution Location Relationship
NRG1 H3K36me3 (-2000, 2000) Promoter Up(-)
H3K79me2 (-2000, 2000) Promoter Up(-)
H3K27ac chr8 (32160722,32169731bp)(32184473,32194301bp) super enhancer Up(-)
H3K9ac chr8 (32160722,32169731bp)(32184473,32194301bp) super enhancer Up(-)
GADD45A H3K36me3 (1600, 2000) Promoter Up(-)
H3K79me2 (TSS, 1200) Promoter Up(-)
H3K27ac chr1 (68035589,68037461bp)(68040917,68042777bp) super enhancer Up(-)
H3K9ac chr1 (68035589,68037461bp)(68040917,68042777bp) super enhancer Up(-)

Proto-oncogenes and important distribution regions of histone modification signals that related to BRCA.

✦ "Up" for high degree of histone modification,"Down" for low degree of histone modification.
✦ "HM" for Histone Modification.
✦"+" for upregulated expression of the corresponding gene,"-" for the corresponding gene down-regulated expression.
✦In the graph of "Distribution", blue is the distribution of histone modifications in HMEC cells and red is the distribution of histone modifications in MCF-7 cells
Gene HM Distribution Location Relationship
TPD52 H3K36me3 (-400, 1400) Promoter Up(+)
H3K79me2 (400, 1200) Promoter Up(+)
H3K27ac chr8 (80989405,80996173bp)(81014221,81017206bp) super enhancer Up(+)
H3K9ac chr8 (80989405,80996173bp)(81014221,81017206bp) super enhancer Up(+)

Tumor suppressor genes and important distribution regions of histone modification signals that related to BRCA.

✦ "Up" for high degree of histone modification,"Down" for low degree of histone modification.
✦ "HM" for Histone Modification.
✦"+" for upregulated expression of the corresponding gene,"-" for the corresponding gene down-regulated expression.
✦In the graph of "Distribution", blue is the distribution of histone modifications in HMEC cells and red is the distribution of histone modifications in MCF-7 cells
Gene HM Distribution Location Relationship
NRG1 H3K36me3 (-2000, 2000) Promoter Up(-)
H3K79me2 (-2000, 2000) Promoter Up(-)
H3K27ac chr8 (32160722,32169731bp)(32184473,32194301bp) super enhancer Up(-)
H3K9ac chr8 (32160722,32169731bp)(32184473,32194301bp) super enhancer Up(-)
GADD45A H3K36me3 (1600, 2000) Promoter Up(-)
H3K79me2 (TSS, 1200) Promoter Up(-)
H3K27ac chr1 (68035589,68037461bp)(68040917,68042777bp) super enhancer Up(-)
H3K9ac chr1 (68035589,68037461bp)(68040917,68042777bp) super enhancer Up(-)
暂无

By analyzing histone modification levels of differentially expressed genes between human breast cancer cells (MCF-7) and human normal mammary epithelial cells (HMEC), the following conclusions were obtained:

  • ➤ Elevated levels of H3K79me2 modification downstream of TSS lead to upregulated gene expression.
  • ➤ Elevated levels of H3K27ac in TSS flanking modifications lead to down-regulated gene expression.
  • ➤ GADD45A and NRG1 are protective factors for breast cancer, and TPD52 is a risk factor for breast cancer.
The histone modification with the greatest importance coefficient in each bin.
✦Divide TSS upstream and downstream 5kb into 100bin
Distribution of histone modification and transcription factor binding strength in the region from 10kb upstream to 2kb downstream of the transcription start site for up- and down-regulated genes in MCF7 and HMEC cell lines. lines.
✦(A) The distribution map of the modification levels of 11 histone modifications and 1 transcription factor for down-regulated genes in MCF7 and HMEC cell lines.
✦(B) The distribution map of the modification levels of 11 histone modifications and 1 transcription factor for up-regulated genes in MCF7 and HMEC cell
The distribution of histone modification and transcription factor binding strength in the region from 10kb upstream to 2kb downstream of the transcription start site for up- and down-regulated IRG genes in MCF7 and HMEC cell lines.
✦(A) The distribution map of the modification levels of 11 histone modifications and 1 transcription factor for down-regulated IRG genes in MCF7 and HMEC cell lines.
✦(B) The distribution map of the modification levels of 11 histone modifications and 1 transcription factor for up-regulated IRG genes in MCF7 and HMEC cell lines.

Key proto-oncogenes that are significantly correlated with prognosis.

✦ "Up" for high degree of histone modification,"Down" for low degree of histone modification.
✦ "HM" for Histone Modification.
✦"+" for upregulated expression of the corresponding gene,"-" for the corresponding gene down-regulated expression.
✦In the graph of "Distribution", blue is the distribution of histone modifications in HMEC cells and red is the distribution of histone modifications in MCF-7 cells
Gene HM Distribution Location Relationship
TPD52 H3K36me3 (-400, 1400) Promoter Up(+)
H3K79me2 (400, 1200) Promoter Up(+)
H3K27ac chr8 (80989405,80996173bp)(81014221,81017206bp) super enhancer Up(+)
H3K9ac chr8 (80989405,80996173bp)(81014221,81017206bp) super enhancer Up(+)

Key tumor suppressor genes that are significantly correlated with prognosis.

✦ "Up" for high degree of histone modification,"Down" for low degree of histone modification.
✦ "HM" for Histone Modification.
✦"+" for upregulated expression of the corresponding gene,"-" for the corresponding gene down-regulated expression.
✦In the graph of "Distribution", blue is the distribution of histone modifications in HMEC cells and red is the distribution of histone modifications in MCF-7 cells
Gene HM Distribution Location Relationship
NRG1 H3K36me3 (-2000, 2000) Promoter Up(-)
H3K79me2 (-2000, 2000) Promoter Up(-)
H3K27ac chr8 (32160722,32169731bp)(32184473,32194301bp) super enhancer Up(-)
H3K9ac chr8 (32160722,32169731bp)(32184473,32194301bp) super enhancer Up(-)
GADD45A H3K36me3 (1600, 2000) Promoter Up(-)
H3K79me2 (TSS, 1200) Promoter Up(-)
H3K27ac chr1 (68035589,68037461bp)(68040917,68042777bp) super enhancer Up(-)
H3K9ac chr1 (68035589,68037461bp)(68040917,68042777bp) super enhancer Up(-)

Lncrnas that act synergistically with methylation on target genes:

SRHC HULC PCAT-14 HOTAIR BZRAP1-AS1 FENDRR HOXA11-AS

Conclusion

Long noncoding RNA SRHC is highly expressed in normal liver tissue, but its expression in HCC is significantly reduced or lacking.Overexpression of this long noncoding RNA can inhibit cancer cell proliferation.Cloning experiments confirmed that, after overexpression of the gene,the clone-forming ability of cancer cells significantly decreases.The promoter region of SRHC contains a CpG-rich island and that SRHC is down-regulated in tumors at least partly by DNA methylation.

Regulatory Mechanism

Conclusion

HULC elicits the methylation of CpG islands in the miR-9 promoter, resulting in the suppression of miR-9 expression. MiR-9 is able to target the 3’UTR of transcription factor PPARA, and the decrease in miR-9 leads to upregulation of PPARA and the subsequent transactivation of ACSL1, which enhances lipogenesis and enriches intracellular triglycerides and cholesterol in hepatoma cells. Thus, HULC-enhanced abnormal lipid metabolism accelerates the growth of liver cancer.Furthermore, the cholesterol product of ACSL1 upregulates HULC by activating the transcription factor RXRA, forming a positive feedback loop with HULC/miR-9/PPARA/ACSL1/cholesterol/RXRA/HULC in hepatoma cells.

Regulatory Mechanism

Conclusion

HCC tissues and cells express high levels of PCAT-14, PCAT-14 inhibits miR-372 expression by inducing the methylation of CpG islands in the miR-372 promoter. ATAD2 is one of the target genes of miR-372, and regulates the Hh pathway to influence HCC proliferation and metastasis. PCA T-14 regulates A TAD2 expression and Hedgehog pathway via miR-372. Together, these findings indicate that PCA T-14 plays an important role in HCC carcinogenesis and may provide a new target for HCC detection and treatment.

Regulatory Mechanism

Conclusion

HOTAIR in HCC cells decreased DNA methylation level of miR-122 promoter region, resulting in elevated expression of miR-122.HOTAIR could upregulate DNMTs expression via EZH2, contributing to modulation of DNA methylationat the miR-122 promoter region and consequently suppression of miR-122 expression.As a well-known tumor suppressor against HCC, miR-122 has been reported to inhibit cell growth and suppress tumorigenesis by negatively regulating its targetsCyclin G1, a key cell cycle protein, plays an essential role in tumor growth, has been shown to be a target of miR-122, and highly expressed in HCC cells.MiR-122 negatively regulated Cyclin G1 expression in HCC cells.HOTAIR upregulated Cyclin G1 expression via suppression of miR-122, implicating that HOTAIR would play an important role in cell cycle regulation through the miR-122/Cyclin G1 pathway.

Regulatory Mechanism

Conclusion

BZRAP1-AS1 was observed to recruit DNMT3b on the promoter region of THBS1, by which BZRAP1-AS1 can induce THBS1 DNA methylation, thereby repressing the transcription of THBS1.BZRAP1-AS1 silencing impedes tumor angiogenesis through increase of THBS1 BZRAP1-AS1 can be a potential therapeutic target to restrain tumor growth in HCC.

Regulatory Mechanism

Conclusion

FENDRR bound to the promoter region of GPC3. The interaction of FENDRR with GPC3 promoter led to methylation of its promoter region. It has been known that methylation is sufficient to silence the GPC3 promoter, which resulted in transcriptional repression of GPC3 expression. FENDRR inhibited HCC growth and invasiveness, at least partially through targeting GPC3 at the epigenetic level. Restoration of FENDRR may be a potential approach to prevent HCC progression and metastasis.

Regulatory Mechanism

Conclusion

HOXA11-AS silencing promotes HOXA11 expression and inhibits the Wnt signaling pathway, subsequently reducing HCC stem cell proliferation, invasion, and self-renewal. These findings demonstrate a novel regulatory mechanism by which HOXA11-AS recruits DNMT1 to methylate the HOXA11 promoter, thus repressing HOXA11 transcription.

Regulatory Mechanism

Lncrnas that act synergistically with histone modification on target genes:

Methylation:

 UCA1 GAS8-AS1 HOTAIR TRERNA1 DLX6-AS1 LINC01419

Acetylation:

 GPC3 Lnc-Myd88

Conclusion

UCA1 was one of the most upregulated lncRNAs by HBx.UCA1 repressed p27 expression via recruiting EZH2 and elevating its 3MeK27H3 level across the promoter via RIP and CHIP assays.UCA1, upregulated by HBx, displayed a crucial role in G1/S transition in both hepatic and hepatoma cells. More importantly, a positive correlation between the expression of UCA1 and HBx and a negative correlation between UCA1 and p27 were observed in HCC specimens, suggesting the significance of UCA1 in HBx-mediated hepatocarinogenesis.

Regulatory Mechanism

Conclusion

LncRNA HOTAIR which recruits the polycomb repressive complex 2 with its H3 lysine27 histone methylation activity, is overexpressed and decreases the expression of miR-122 in HCC tissues. As a well-known oncogene in most tumors, both in vitro and in vivo experiments demonstrated that knockdown of HOTAIR inhibited HCC cells proliferation, induced cell cycle arrest and suppressed tumor progression by negatively regulating miR-122 and consequently suppressing Cyclin G1.

Regulatory Mechanism

Conclusion

LncRNA GAS8-AS1 is required to maintain the GAS8 promoter in an open chromatin state. In accord with this notion, knockdown of GAS8-AS1 results in reduced MLL1/WDR5 binding, decreased H3K4me3 levels, diminished RNA Pol II functions, and gene silencing of GAS8. Thus, lncRNA GAS8-AS1 may function as part of a surveillance mechanism that maintains activation of GAS8 promoter and transcription, which thus prevents carcinogenesis.

Regulatory Mechanism

Conclusion

TRERNA1 recruited EHMT2 to dimethylate H3K9 in the CDH1 promoter region. Given that lncRNAs are involved in histone methylation modification, they have become important epigenetic regulatory molecules during the regulation of target genes. EHMT2, a major histone methyltransferase for H3K9 me2, is a crucial modifying factor that is regulated during gene silencing. SNAI1 acts as a repressor of CDH1 and binds to EHMT2, which indicates that EHMT2 decreases CDH1 expression not only by dimethylation but also by interacting with SNAI1. In a transwell assay, TRERNA1 enhanced the metastatic ability of SNAI1 in HCC cells.In summary , The elevated lncRNA TRERNA1 levels promoted HCC cell metastasis in vitro and in vivo, the aberrant expression of TRERNA1 relates to metastatic HCC and a poor prognosis for patients. TRERNA1 suppresses CDH1 with epigenetic histone modifications via the recruitment of EHMT2 and/ or the EHMT2/SNAI1 complex. Therefore, targeting the lncRNA TRERNA1 might be a novel therapeutic strategy for metastatic HCC.

Regulatory Mechanism

Conclusion

CADM1, a member belonging to the immunoglobulin superfamily of cell adhesion molecule, is an extensively known tumor suppressor.LncRNA DLX6-AS1 was able to lead to a reduction in CADM1 expression by increasing CADM1 methylation, thus activating the STAT3 signaling pathway. STAT3 is a potent modulator of tumorigenesis, survival, and inflammation of liver cells, is constitutively activated in the vast majority of HCC cells.Silencing of lncRNA DLX6-AS1 enforced the expression of CADM1 and inactivated the STAT3 signaling pathway by suppressing CADM1 promoter methylation, thus repressing the tumorigenesis and tumor progression of LCSCs.

Regulatory Mechanism

Conclusion

The LINC01419-EZH2 complex transcriptionally decreases RECK expression by binding at its H3K27me3 promoter.This contributes to HCC cell proliferation and metastasis.Elevated LINC01419 expression level results in poor outcomes in HCC. LINC01419 potentially suppresses RECK expression epigenetically via EZH2. LINC01419 upregulation is induced by the transcription activation of cjun. These findings proved that LINC01419 could provide a theoretical basis for clinical diagnosis and treatment of hepatocellular carcinoma.

Regulatory Mechanism

Conclusion

Lnc-Myd88 was located upstream of the protein-coding gene Myd88, and presented a reverse transcription direction with Myd88. On account of the results of ChIP assays conducted above, Lnc-Myd88 showed a positive correlation with the enrichment of H3K27Ac in the promoter region of Myd88, indicating that Lnc-Myd88 might regulate Myd88 expression through histone modifications.Lnc-Myd88 enhanced Myd88 expression through increasing the enrichment of H3K27Ac in the promoter region and then activated the NF-κB and PI3K/AKT signal pathways and then promoting the proliferation and metastasis of HCC both in vitro and in vivo.

Regulatory Mechanism

Conclusion

GPC3-AS1 and GPC3 expression in an independent cohort of HCC tissues.GPC3-AS1 and GPC3 are both upregulated in HCC tissues.GPC3-AS1 upregulation is associated with AFP, tumor size, microvascular invasion, encapsulation, and BCLC stage.GPC3-AS1 upregulates the transcription of GPC3, but does not change GPC3 mRNA stability.RNA pull-down, RIP, and ChIP assays showed that GPC3-AS1 physically associates with PCAF and recruits PCAF to the GPC3 gene body region. PCAF is a well-known histone acetyltransferase, which has important roles in transcription elongation.GPC3-AS1 binds to and recruits PCAF to the GPC3 gene body region, and upregulates GPC3 transcription. Through upregulating GPC3 expression, GPC3-AS1 enhances HCC cell proliferation and migration. These findings indicate that GPC3-AS1 could be a potential therapeutic target for HCC.

Regulatory Mechanism

Lncrnas that act synergistically with histone transcription factor on target genes:

ANRIL TUG1

Conclusion

LncRNA ANRIL whose expression is significantly upregulated in HCC tissues compared with normal tissues.Increased ANRIL expression was correlated with HCC tumor size and BCLC stage, which suggests that ANRIL may play a key role in HCC development and progression.ANRIL could bind with both EZH2 and SUZ12 in HCC cells. Furthermore, bioinformatics analysis indicated that KLF2 could be a new ANRIL downstream target, and knockdown of ANRIL, EZH2 and SUZ12 expression indeed both up-regulated KLF2 expression levels in HCC cells. In addition, ChIP assays also demonstrated that EZH2 could directly bind to KLF2 promoter region and inhibition of ANRIL decreased its binding ability. ANRIL could repress KLF2 transcription by binding with EZH2 and SUZ12 and recruitment of PRC2 to the KLF2 gene locus in HCC cells.The Kruppel-like factor (KLF) family which consists of a set of transcription factors that have been identified in diverse organisms functions in cell differentiation and proliferation.

Regulatory Mechanism

Conclusion

LncRNA TUG1 whose expression is significantly upregulated in HCC tissues compared with normal tissues.Increased TUG1 expression was correlated with HCC tumor size and BCLC stage, which suggests that TUG1 may play a key role in HCC development and progression.TUG1 could bind with both EZH2 and SUZ12 in HCC cells. Furthermore, bioinformatics analysis indicated that KLF2 could be a new TUG1 downstream target, and knockdown of TUG1, EZH2 and SUZ12 expression indeed both up-regulated KLF2 expression levels in HCC cells. In addition, ChIP assays also demonstrated that EZH2 could directly bind to KLF2 promoter region and inhibition of TUG1 decreased its binding ability. TUG1 could repress KLF2 transcription by binding with EZH2 and SUZ12 and recruitment of PRC2 to the KLF2 gene locus in HCC cells.The Kruppel-like factor (KLF) family which consists of a set of transcription factors that have been identified in diverse organisms functions in cell differentiation and proliferation.

Regulatory Mechanism

Lncrnas acting on target genes alone:

SOX21-AS1

Conclusion

Silenced SOX21-AS1 suppressed cell proliferation and metastasis, resulted in cell cycle arrest, and induced apoptosis in hepatocellular carcinoma. Mechanically, RIP was conducted to prove that SOX21-AS1 could bind with EZH2. ChIp assay was carried out and manifested that SOX21-AS1 epigenetically silenced p21 via recruiting EZH2 to the promoter of p21 to affect hepatocellular carcinoma progression.

Regulatory Mechanism

Lncrnas that act synergistically with RNA methylation on target genes:

H19

Conclusion

A regulatory axis:MYC-NSUN2-H19G3BP1-MYC. In tumors, high expression of NSUN2 leads to increased methylation levels of H19 RNA. Hypermethylated H19 RNA may competitively bind to G3BP1, which further delays MYC mRNA decay and leads to a further increase in MYC levels, resulting in consequent deterioration of tumors.H19 RNA is a specific target for the NSUN2 modifier. The m5C-modified H19 lncRNA may promote the occurrence and development of tumors by recruiting the G3BP1 oncoprotein.

Regulatory Mechanism

Lncrnas that act synergistically with methylation, histone modifications, and transcription factors on target genes:

Linc00441

Conclusion

Linc00441 share a bidirectional promoter with RB1.Aberrant upregulated intranuclear Linc00441 was inversely correlated with RB1 expression in human HCC samples. In vitro experiments, overexpression of Linc00441 could decrease the expression level of TSG RB1.Linc00441 may decrease RB1 expression through enhanced CpG islands methylation in the promoter of RB1 gene by DNMT3A recruitment, and afterward, causing proliferation of HCC in both in vitro and in vivo. TCF-4 and H3K27 acetylation also contributed to Linc00441 upregulation.

Regulatory Mechanism