+ Site Statistics
References:
54,258,434
Abstracts:
29,560,870
PMIDs:
28,072,757
+ Search Articles
+ Subscribe to Site Feeds
Most Shared
PDF Full Text
+ PDF Full Text
Request PDF Full Text
+ Follow Us
Follow on Facebook
Follow on Twitter
Follow on LinkedIn
+ Translate
+ Recently Requested

The histone methyltransferase G9a: a new therapeutic target in biliary tract cancer



The histone methyltransferase G9a: a new therapeutic target in biliary tract cancer



Human Pathology 72: 117-126



The histone methyltransferase G9a (EHMT2) is a key enzyme for dimethylation of lysine 9 at histone 3 (H3K9me2), a suppressive epigenetic mark. G9a is over-expressed in tumor cells and contributes to cancer aggressiveness. Biliary tract cancer (BTC) is a rare cancer with dismal prognosis due to a lack of effective therapies. Currently, there are no data on the role of G9a in BTC carcinogenesis. We analyzed G9a expression in n=68 BTC patient specimens and correlated the data with clinicopathological and survival data. Moreover, we measured G9a expression in a panel of BTC cell lines and evaluated the cytotoxic effect of G9a inhibition in BTC cells using established small-molecule G9a inhibitors. G9a was considerably expressed in about half of BTC cases and was significantly associated with grading and tumor size. Additionally, we observed significant differences of G9a expression between growth type and tumor localization groups. G9a expression diametrically correlated with Vimentin (positive) and E-Cadherin (negative) expression. Importantly, survival analysis revealed G9a as a significant prognostic factor of poor survival in patients with BTC. In BTC cells, G9a and H3K9me2 were detectable in a cell line-dependent manner on mRNA and/or protein level, respectively. Treatment of BTC cells with established small-molecule G9a inhibitors resulted in reduction of cell viability as well as reduced G9a and H3K9me2 protein levels. The present study strongly suggests that G9a contributes to BTC carcinogenesis and may represent a potential prognostic factor as well as a therapeutic target.

(PDF emailed within 0-6 h: $19.90)

Accession: 060354268

Download citation: RISBibTeXText

PMID: 29133140

DOI: 10.1016/j.humpath.2017.11.003


Related references

Histone Methyltransferase EZH2: A Therapeutic Target for Ovarian Cancer. Molecular Cancer Therapeutics 17(3): 591-602, 2018

Role of the EZH2 histone methyltransferase as a therapeutic target in cancer. Pharmacology and Therapeutics 165: 26-31, 2017

The histone methyltransferase G9a as a therapeutic target to override gemcitabine resistance in pancreatic cancer. Oncotarget 7(38): 61136-61151, 2016

Validation of the histone methyltransferase EZH2 as a therapeutic target for various types of human cancer and as a prognostic marker. Cancer Science 102(7): 1298-1305, 2011

Src as a Therapeutic Target in Biliary Tract Cancer. Molecular Cancer Therapeutics 15(7): 1515-1524, 2017

Consistent overexpression of fatty acid synthase in biliary tract carcinomas A novel target for anti-biliary tract cancer drug development?. Laboratory Investigation 81(1): 192A, 2001

Pygo2 associates with MLL2 histone methyltransferase and GCN5 histone acetyltransferase complexes to augment Wnt target gene expression and breast cancer stem-like cell expansion. Molecular and Cellular Biology 30(24): 5621-5635, 2011

The histone methyltransferase EZH2 is a therapeutic target in small cell carcinoma of the ovary, hypercalcaemic type. Journal of Pathology 242(3): 371-383, 2017

PI3K-mTOR pathway identified as a potential therapeutic target in biliary tract cancer using a newly established patient-derived cell panel assay. Japanese Journal of Clinical Oncology 48(4): 396-399, 2018

The histone methyltransferase DOT1L: regulatory functions and a cancer therapy target. American Journal of Cancer Research 5(9): 2823-2837, 2015

Loss of DNA methylation and histone H4 lysine 20 trimethylation in human breast cancer cells is associated with aberrant expression of DNA methyltransferase 1, Suv4-20h2 histone methyltransferase and methyl-binding proteins. Cancer Biology & Therapy 5(1): 65-70, 2006

Loss of DNA methylation and histone H4 lysine 20 trimethylation in human breast cancer cells is associated with aberrant expression of DNA methyltransferase 1, Suv4-20h2 histone methyltransferase and methyl-binding proteins. Cancer Biology and Therapy 5(1): 65-70, 2005

The histone methyltransferase EZH2 as a druggable target in SHH medulloblastoma cancer stem cells. Oncotarget 8(40): 68557-68570, 2017

Triptolide inhibits histone methyltransferase EZH2 and modulates the expression of its target genes in prostate cancer cells. Asian Pacific Journal of Cancer Prevention 14(10): 5663-5669, 2015

Oncogenic histone methyltransferase EZH2: A novel prognostic marker with therapeutic potential in endometrial cancer. Oncotarget 8(25): 40402-40411, 2017