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Hum Pathol. 2018 Feb;72:117-126. doi: 10.1016/j.humpath.2017.11.003. Epub 2017 Nov 11.

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

Author information

1
Laboratory for Tumour Biology and Experimental Therapies (TREAT), Institute of Physiology and Pathophysiology, Paracelsus Medical University, 5020 Salzburg, Austria; Department of Internal Medicine I, Paracelsus Medical University / Salzburger Landeskliniken (SALK), 5020 Salzburg, Austria. Electronic address: ch.mayr@salk.at.
2
Laboratory for Tumour Biology and Experimental Therapies (TREAT), Institute of Physiology and Pathophysiology, Paracelsus Medical University, 5020 Salzburg, Austria; Laboratory of Functional and Molecular Membrane Physiology (FMMP), Institute of Physiology and Pathophysiology, Paracelsus Medical University, 5020 Salzburg, Austria. Electronic address: katharina.helm@stud.pmu.ac.at.
3
Laboratory of Functional and Molecular Membrane Physiology (FMMP), Institute of Physiology and Pathophysiology, Paracelsus Medical University, 5020 Salzburg, Austria. Electronic address: martin.jakab@pmu.ac.at.
4
Laboratory for Tumour Biology and Experimental Therapies (TREAT), Institute of Physiology and Pathophysiology, Paracelsus Medical University, 5020 Salzburg, Austria; Laboratory of Functional and Molecular Membrane Physiology (FMMP), Institute of Physiology and Pathophysiology, Paracelsus Medical University, 5020 Salzburg, Austria; Department for Radon Therapy Research, Ludwig Boltzmann Cluster for Arthritis and Rehabilitation, Institute of Physiology and Pathophysiology, Paracelsus Medical University, 5020 Salzburg, Austria. Electronic address: markus.ritter@pmu.ac.at.
5
Cancer Research Unit, Research and Development Department, Dhulikhel Hospital, Kathmandu University, 45200 Dhulikhel, Nepal. Electronic address: rmaleku@hotmail.com.
6
Department of Pathology, Dhulikhel Hospital, Kathmandu University Hospital, 45200 Dhulikhel, Nepal. Electronic address: makajuram@yahoo.com.
7
Department of Internal Medicine I, Paracelsus Medical University / Salzburger Landeskliniken (SALK), 5020 Salzburg, Austria. Electronic address: and.wagner@salk.at.
8
Division of Oncology, Department of Internal Medicine, Medical University of Graz, 8036 Graz, Austria; Department of Experimental Therapeutics, The UT MD Anderson Cancer Center, Houston, TX 77030, USA. Electronic address: martin.pichler@medunigraz.at.
9
Laboratory for Tumour Biology and Experimental Therapies (TREAT), Institute of Physiology and Pathophysiology, Paracelsus Medical University, 5020 Salzburg, Austria; Laboratory of Functional and Molecular Membrane Physiology (FMMP), Institute of Physiology and Pathophysiology, Paracelsus Medical University, 5020 Salzburg, Austria. Electronic address: marlena.beyreis@pmu.ac.at.
10
Department of Visceral, Transplant and Thoracic Surgery, Medical University Innsbruck, 6020 Innsbruck, Austria. Electronic address: stefan.staettner@tirol-kliniken.at.
11
Department of Surgery, Paracelsus Medical University / Salzburger Landeskliniken (SALK), 5020 Salzburg, Austria. Electronic address: ta.jaeger@salk.at.
12
Institute of Pathology, Cancer Cluster Salzburg, Paracelsus Medical University / Salzburger Landeskliniken (SALK), 5020 Salzburg, Austria. Electronic address: e.klieser@salk.at.
13
Laboratory for Tumour Biology and Experimental Therapies (TREAT), Institute of Physiology and Pathophysiology, Paracelsus Medical University, 5020 Salzburg, Austria; Department of Internal Medicine I, Paracelsus Medical University / Salzburger Landeskliniken (SALK), 5020 Salzburg, Austria. Electronic address: t.kiesslich@salk.at.
14
Institute of Pathology, Cancer Cluster Salzburg, Paracelsus Medical University / Salzburger Landeskliniken (SALK), 5020 Salzburg, Austria. Electronic address: d.neureiter@salk.at.

Abstract

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.

KEYWORDS:

Biliary tract cancer; Epigenetics; G9a; H3K9me2; Histone methyltransferase

PMID:
29133140
DOI:
10.1016/j.humpath.2017.11.003
[Indexed for MEDLINE]

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