Increased expression of EHMT2 associated with H3K9me2 level contributes to the poor prognosis of gastric cancer

Abstract

Di-methylated lysine 9 of histone H3 (H3K9me2), regulated by histone methyltransferases, is involved in the epigenetic regulation of tumor-associated genes. The present study aimed to evaluate whether the H3K9me2 methylation level is associated with the expression level of euchromatic histone lysine methyltransferase 2 (EHMT2) in the prognosis of gastric cancer (GC). H3K9me2 methylation level and EHMT2 expression level were detected by immunohistochemistry in 118 GC samples. The clinicopathological significance of H3K9me2 and EHMT2 in patients with GC was assessed using a paired Student's t-test, χ 2 test, Kaplan-Meier analysis with a log-rank test and Cox's proportional hazard analysis. Strong positive immunostaining of H3K9me2 and EHMT2 was observed in cancerous tissues compared with adjacent non-cancerous tissues. Positive immunostaining of EHMT2 and H3K9me2 was associated with lymph node metastasis, pathological grade and tumor-node-metastasis stage. H3K9me2 expression level was increased in tumor tissue and associated with worse specific-disease and disease-free survival time. In addition, EHMT2 protein expression levels were associated with the expression levels of H3K9me2. Low expression levels of H3K9me2 and EHMT2 predicted a better prognosis of patients with GC. The survival time of patients with a high expression of H3K9me2 and/or EHMT2 was significantly shorter compared with that of the patients with a low expression of H3K9me2 and/or EHMT2. In conclusion, an overexpression pattern of H3K9me2 and/or EHMT2 may be associated with clinicopathological features of GC and may be predictor markers of progression and prognosis in patients with GC, in addition to putative therapeutic targets.

Structure, Activity, and Function of the Protein Lysine Methyltransferase G9a

“…These epigenetic modifications, which result in altered chromatin structure and gene expression were reported in different types of cancers [ 108 ] ( Figure 3 ). G9a was overexpressed in breast, gastric, ovarian, cervical, endometrial, prostate, lung, colorectal, liver, urinary bladder, and brain cancers, as well as in hematological malignancies, melanoma, and cholangiocarcinoma, leading to aberrant H3K9 methylation [ 109 , 110 , 111 , 112 , 113 , 114 , 115 , 116 , 117 , 118 , 119 , 120 , 121 , 122 ]. One of the main reasons for this increase in G9a expression and H3K9 methylation is hypoxia [ 103 ].…”

Chromatin and noncoding RNA-mediated mechanisms of gastric tumorigenesis

“…Analysis of TCGA data showed that a number of histone modifiers are differentially expressed between GC and noncancer samples 28 . A more recent analysis of TCGA data focusing on HMTs found that the increased expression of G9a/ EHMT2, an H3K9 methyltransferase, is associated with poor prognosis, while its oncogenic effect may be mediated by activating the expression of MTOR via increasing promoter H3K9me1 [29][30][31] .…”

Epigenetic regulation of autophagy: A key modification in cancer cells and cancer stem cells

“…Immunohistochemistry data of paired lung adenocarcinoma and lung squamous cell carcinoma samples revealed a significant higher expression of G9a correlating with metastasis and a poor prognosis of patients[ 166 ]. In comparison, low expressions of H3K9me2 and G9a could predict a better prognosis for patients with gastric cancer[ 167 ].…”