Histone Variant H2A.Z.2 Mediates Proliferation and Drug Sensitivity of Malignant Melanoma

Abstract

SUMMARY Histone variants are emerging as key regulatory molecules in cancer. Here we report a novel role for the H2A.Z isoform H2A.Z.2 as a driver of malignant melanoma. H2A.Z.2 is highly expressed in metastatic melanoma, correlates with decreased patient survival, and is required for cellular proliferation. Our integrated genomic analyses reveal that H2A.Z.2 controls the transcriptional output of E2F target genes in melanoma cells. These genes are highly expressed and display a distinct signature of H2A.Z occupancy. We identify BRD2 as an H2A.Z interacting protein, whose levels are also elevated in melanoma. We further demonstrate that H2A.Z.2 regulated genes are bound by BRD2 and E2F1 in a H2A.Z.2-dependent manner. Importantly, H2A.Z.2 deficiency sensitizes melanoma cells to chemotherapy and targeted therapies. Collectively, our findings implicate H2A.Z.2 as a mediator of cell proliferation and drug sensitivity in malignant melanoma, holding translational potential for novel therapeutic strategies.

The Role of Bromodomain and Extraterminal Motif (BET) Proteins in Chromatin Structure

“…It is possible that BRD2 may promote high levels of transcription at certain boundaries. In addition, BRD2 was recently reported to bind the histone variant H2A.Z (Vardabasso et al 2015;Surface et al 2016), which is enriched in the nucleosomes arrayed around CTCF sites (Fu et al 2008), suggesting that it might contribute to structural features of boundary regions.…”

Genetic complementation analysis showed distinct contributions of the N‐terminal tail of H2A.Z to epigenetic regulations

“…H2A.Z is also reported to play important roles in various biological phenomena. For example, H2A.Z is required for ES cell pluripotency and differentiation (Creyghton et al, 2008;Wang et al, 2015), and over-expression of H2A.Z has been observed in several types of cancer cells, including breast cancer, bladder cancer, and malignant melanoma cells (Hua et al, 2008;Kim et al, 2013;Vardabasso et al, 2015).Although certain features of H2A.Z, which are distinct from those of the canonical H2A, are thought to contribute to various functions orchestrated by H2A.Z, their identities remained unknown so far.non-allelic histone variants (Talbert et al, 2010; Talbert et al, 2012). Although the canonical histones are mainly expressed and incorporated into the chromatin during the S-phase of the cell cycle (Marzluff et al, 2008), the expression and incorporation of the histone variants are not restricted to S-phase (Talbert et al, 2012).…”

“…H2A.Z is also over-expressed in tumor cells (Hua et al, 2008;Kim et al, 2013;Vardabasso et al, 2015), and there is a study that described the relevance between acetylation of H2A.Z and transcriptional dysregulation in tumor cells (Va l d é s -Mora et al, 2012). Thus, H2A.Z has been proposed to be a potential molecular target for developing therapeutic strategies (Rangasamy, 2010;Vardabasso et al, 2015). Taken together with the results described here, results of the above cited reports imply that H2A.Z functions through multiple inter-molecular interactions with various chromatin proteins.…”

Histone variant H2A.Z.2: A novel driver of melanoma progression

“…6 Recently, we have reported a role for another variant of the H2A family, namely H2A.Z.2, in promoting proliferation of melanoma cells. 7 H2A.Z is a highly conserved H2A variant with a well-established role in transcriptional regulation. Two distinct H2A.Z isoforms, H2A.Z.1 and H2A.Z.2, have been identified in the vertebrate genome as products of 2 non-allelic genes that differ by only 3 amino acids.…”