Expression and functionality of histone H2A variants in cancer

// Fatima Liliana Monteiro 1 , Tiago Baptista 2 , Francisco Amado 1 , 3 , Rui Vitorino 1 , Carmen Jeronimo 2,4 and Luisa A. Helguero 1 1 Mass Specrometry Center, Organic Chemistry and Natural Products Unit (QOPNA), Dep. of Chemistry, Universidade de Aveiro., Aveiro, Portugal 2 Cancer Biology & Epigenetics Group, Research Center Portuguese Oncology Institute – Porto. Porto, Portugal 3 School of Health Sciences, Universidade de Aveiro., Portugal 4 Department of Pathology and Molecular Immunology, Institute of Biomedical Sciences Abel Salazar (ICBAS) – University of Porto, Porto, Portugal Correspondence: Luisa A. Helguero, email: // Keywords : epigenetics, post-translational modifications, histone H2A, cancer. Received : April 8, 2014 Accepted : May 24, 2014 Published : May 26, 2014 Abstract Regulation of gene expression includes the replacement of canonical histones for non-allelic histone variants, as well as their multiple targeting by postranslational modifications. H2A variants are highly conserved between species suggesting they execute important functions that cannot be accomplished by canonical histones. Altered expression of many H2A variants is associated to cancer. MacroH2A variants are enriched in heterocromatic foci and are necessary for chromatin condensation. MacroH2A1.1 and macroH2A1.2 are two mutually exclusive isoforms. MacroH2A1.1 and macroH2A2 inhibit proliferation and are associated with better cancer prognosis; while macroH2A1.2 is associated to cancer progression. H2AX variant functions as a sensor of DNA damage and defines the cellular response towards DNA repair or apoptosis; therefore, screening approaches and therapeutic options targeting H2AX have been proposed. H2A.Z is enriched in euchromatin, acting as a proto-oncogene with established roles in hormone responsive cancers and overexpressed in endocrine-resistant disease. Other H2A family members have also been found altered in cancer, but their function remains unknown. Substantial progress has been made to understand histone H2A variants, their contribution to normal cellular function and to cancer development and progression. Yet, implementation of high resolution mass spectrometry is needed to further our knowledge on highly homologous H2A variants expression and function.