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Table 3 Histone modifications in breast cancer metastasis

From: A three layered histone epigenetics in breast cancer metastasis

S. no.Histone modificationRole in breast cancer metastasisReferences
Methylation
 1.H3K4Oncogene JARID1A/1B interacts with pRb by demethylation of H3K4
Lower expression in basal carcinomas and Her-2 positive tumors
Higher H3K4me3 is associated with breast tumor
H3K4me3 is also regulated via PI3/AKT pathway in breast cancer
H3K4me3 enrichment is found in the promoter of AURKB and E2F2 (AKT target)
PRMT-5 causes H3K4 tri-methylation in the promoter of FOXP1
[124, 125, 135, 136]
 2.H3K27Lower H3K27me3 is associated with breast cancer, tumor size, lymph node stage
H3K27me3 is catalyzed by EZH2 which itself is an important player of EMT
H3K27me3 is found in the promoter region of FOXC1, RAD51, CDH1, RUNX3, FOX-A1
[126,127,128,129,130]
 3.H3K79DOT1L promotes H3K79 methylation
Higher H3K79 methylation is observed in the BCAT1 promoter
Causes genomic instability
Promotes tumorigenesis
[131,132,133,134]
 4.H3R2PRMT-5 causes H3R2 di-methylation in the promoter of FOXP1[136]
 5.H4R3Lower expression in basal carcinomas and Her-2 positive tumors
Associated with lymph node stage
H4R3me2 by PRMT1 causes tumorigenesis
PRMT1 is recruited in the ZEB1 promoter for H4R3 di-methylation
[135, 136]
 6.H2A.Z.1.K101H2A.Z.1.K101 undergoes di-methylation by SYMD3 in Cyclin A1 promoter region[90]
Acetylation
 1.H3H3 acetylation in slug promoter causes EMT in phorbol ester treated MCF-7
PRMT7 causes lowering of H3 acetylation in cdh-1 promoter
FOXM1 is recruited in the VEGF promoter where it causes H3 acetylation thereby promoting angiogenesis
But when FOXO3a is enriched in VEGF promoter it recruits HDAC2 and causes deacetylation therefore repressing VEGF signal
P300 (HAT) causes acetylation of H3 and H4 in ER-α promoter in MCF-7 and therefore active expression. While presence of DNMT in the promoter region of sER-α in MDAMB occludes p300 association thereby repressing it
Association with HER-2 positive breast cancer. H3 and H4 acetylation is mainly found in the promoter region of Her-2 positive cells
[141,142,143,144,145]
 2.H3K4Increased H3K4 acetylation mark is associated with metastatic behavior of sample
H3K4 is enriched in the promoter region of VIM gene in MDAMB
H3K4 mark is observed in the promoter region of GATA3 and FOXA1 in MCF-7 and MCF-10A
[147, 148]
 3.H3K9Low H3K9 mark is associated with lymph stage sample[136]
 4.H3K18Associated with high grade tumour
Enriched in the promoter of EMT specific genes
[147]
 5.H3K27Promotes EMT[147, 150]
 6.H4PRMT7 causes lowering of H4 acetylation in cdh-1 promoter
FOXM1 is recruited in the VEGF promoter where it causes H4 acetylation thereby promoting angiogenesis
[142, 143]
 7.H4K16Low H4K16 mark is associated with lymph stage sample
Positive association with angiogenesis and carcinogenesis
[135, 146]
 8.H2A.ZAcetylated H2A.Z is required for p21 promoter activation in breast cancer cells[149]
Phosphorylation
 1.H2A.XPhosphorylated H2A.X at ser139 i.e. ɣH2A.X is associated with breast cancer metastasis
ɣH2A.X is recruited at DNA repair site upon DSBs
H2A.X tyr39 also has positive correlation with breast cancer
JMJD6 causes phosphorylation of H2A.X at tyr39 to activate autophagy related genes (ATG1B, ATG5 and ATG7) in TNBC
[57, 107]
 2.PhosphoH3Positive correlation between oncotype genotyping test and PhosphoH3 is observed amongst breast cancer patients
Possitive PhosphoH3 level is observed in breast cancer biopsy samples
PhosphoH3 is found to be associated with positive outcome among Asian breast cancer patients
PAK1 causes H3.3 phosphorylation which is implicated in breast cancer
[155,156,157,158,159]
 3.Phospho H1Differential level of phospho histone H1 (pt146) is observed in different breast cancer cell lines[162]
 4.Phospho H4Phospho histone H4 (ser1) is found to be recruited at DSBs[161]
Ubiquitination
 1.H2BubBasal breast cancer has lower H2Bub level while luminal breast cancer has higher H2Bub level
USP-22 causes deubiquitination of H2A and H2B histones. USP-22 has positive association with lymph node metastasis and ki-67 level
[164, 167, 168]
 2.H2AK119ub1Low CRL4B expression leads to cell proliferation and invasion by causing global loss of H2AK119ub1[166]
 3.H2AK127ub1Lower H2AK127ub1 is observed in TNBC[165]
 4.H2BK120ub1Lower H2BK120ub1 is associated with breast cancer[166]
PARylation
 1.H3, H4H3 PARylation decreases EZH2 affinity for H3 resulting in global loss in H3K27 methylation
PARP9 over-expression is associated with breast cancer metastasis
PARP9 enhances doxorubicin resistance via H4 ubiquitination
[170, 171]