title: Identification of a class of human cancer germline genes with transcriptional silencing refractory to the hypomethylating drug 5-aza-2'-deoxycytidine.
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.
authors.affiliation: 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.
authors.forename: Ahmed
authors.initials: A
authors.lastname: Almatrafi
authors.affiliation: Institute for Knowledge Discovery, Graz University of Technology, Graz, Austria ; Core Facility Bioinformatics, Austrian Centre of Industrial Biotechnology, Graz, Austria.
authors.forename: Julia
authors.initials: J
authors.lastname: Feichtinger
authors.affiliation: North West Cancer Research Institute, School of Medical Sciences, Bangor University, Bangor, United Kingdom.
authors.forename: Ellen G
authors.initials: EG
authors.lastname: Vernon
authors.affiliation: North West Cancer Research Institute, School of Medical Sciences, Bangor University, Bangor, United Kingdom.
authors.forename: Natalia Gomez
authors.initials: NG
authors.lastname: Escobar
authors.affiliation: North West Cancer Research Institute, School of Medical Sciences, Bangor University, Bangor, United Kingdom.
authors.forename: Jane A
authors.initials: JA
authors.lastname: Wakeman
authors.affiliation: MRC Functional Genomics Unit, Department of Anatomy, Physiology and Genetics, University of Oxford, Oxford, United Kingdom.
authors.forename: Lee D
authors.initials: LD
authors.lastname: Larcombe
authors.affiliation: North West Cancer Research Institute, School of Medical Sciences, Bangor University, Bangor, United Kingdom.
authors.forename: Ramsay J
authors.initials: RJ
authors.lastname: McFarlane
keywords: cancer/testis antigen; gene silencing; germline gene; hypomethylation; oncogenesis