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Oncoscience. 2014 Nov 10;1(11):745-50. eCollection 2014.

Identification of a class of human cancer germline genes with transcriptional silencing refractory to the hypomethylating drug 5-aza-2'-deoxycytidine.

Author information

1
North West Cancer Research Institute, School of Medical Sciences, Bangor University, Bangor, United Kingdom ; Current address: Department of Biology, Faculty of Science, University of Taibah, Medinah, Saudi Arabia.
2
Institute for Knowledge Discovery, Graz University of Technology, Graz, Austria ; Core Facility Bioinformatics, Austrian Centre of Industrial Biotechnology, Graz, Austria.
3
North West Cancer Research Institute, School of Medical Sciences, Bangor University, Bangor, United Kingdom.
4
MRC Functional Genomics Unit, Department of Anatomy, Physiology and Genetics, University of Oxford, Oxford, United Kingdom.

Abstract

Bona fide germline genes have expression restricted to the germ cells of the gonads. Testis-specific germline development-associated genes can become activated in cancer cells and can potentially drive the oncogenic process and serve as therapeutic/biomarker targets; such germline genes are referred to as cancer/testis genes. Many cancer/testis genes are silenced via hypermethylation of CpG islands in their associated transcriptional control regions and become activated upon treatment with DNA hypomethylating agents; such hypomethylation-induced activation of cancer/testis genes provides a potential combination approach to augment immunotherapeutics. Thus, understanding cancer/testis gene regulation is of increasing clinical importance. Previously studied cancer/testis gene activation has focused on X chromosome encoded cancer/testis genes. Here we find that a sub-set of non-X encoded cancer/testis genes are silenced in non-germline cells via a mechanism that is refractory to epigenetic dysregulation, including treatment with the hypomethylating agent 5-aza-2'-deoxycytidine and the histone deacetylase inhibitor tricostatin A. These findings formally indicate that there is a sub-group of the clinically important cancer/testis genes that are unlikely to be activated in clinical therapeutic approaches using hypomethylating agents and it indicates a unique transcriptional silencing mechanism for germline genes in non-germline cells that might provide a target mechanism for new clinical therapies.

KEYWORDS:

cancer/testis antigen; gene silencing; germline gene; hypomethylation; oncogenesis

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