Expression and functionality of histone H2A variants in cancer

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.

The Histone Chaperones FACT and Spt6 Restrict H2A.Z from Intragenic Locations

“…Fifth, and quite interestingly, H2A.Z has been shown to redistribute to active gene bodies upon B-cell lymphomagenesis (Conerly et al, 2010). Given the established role of H2A.Z in cancer (Dryhurst and Ausio, 2014; Monteiro et al, 2014; Rangasamy, 2010), this raises the possibility that H2A.Z-mediated cryptic transcription may contribute to carcinogenesis. Also in favor of such a model, a recent study established that FACT acts as an “accelerator” of tumor formation (Garcia et al, 2013).…”

“…Also in favor of such a model, a recent study established that FACT acts as an “accelerator” of tumor formation (Garcia et al, 2013). Since high H2A.Z levels have been associated with cancer progression and a negative prognosis (Dryhurst and Ausio, 2014; Monteiro et al, 2014; Rangasamy, 2010), and because aberrant transcription is a well-recognized hallmark of cancer, activation of cryptic transcription by H2A.Z represents a new model for pathological changes to gene expression that merits scrutiny.…”

The characterization of macroH2A beyond vertebrates supports an ancestral origin and conserved role for histone variants in chromatin

“…11,17,22 Additionally, deregulation in macroH2A.1 alternative splicing has been related to the metastatic transition in several types of cancer. [23][24][25] Several in vivo and in vitro studies indicate that macroH2A increases nucleosome stability due to the specific structural features of its H2A domain. 26,27 It has also been shown that the structural changes resulting from the incorporation of macroH2A into nucleosomes prevent the access to chromatin by some remodeling complexes (e.g., SWI/SNF).…”

Extracellular superoxide dismutase and its role in cancer

“…Histone variants mediate a variety of functions, such as modifying expression, controlling chromatin condensation, sensing DNA damage, and controlling the cellular response toward DNA damage repair or apoptosis [186]. MacroH2A isoforms are unique H2A histone variants due to the presence of a 30-kDa non-histone domain (macro domain) at their C-termini.…”