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

Chiara Vardabasso, Alexandre Gaspar-Maia, Dan Hasson, Sebastian Pünzeler, David Valle-Garcia, Tobias Straub, Eva C. Keilhauer, Thomas Strub, Joanna Dong, Taniya Panda, Chi Yeh Chung, Jonathan L. Yao, Rajendra Singh, Miguel F. Segura, Barbara Fontanals-Cirera, Amit Verma, Matthias Mann, Eva Hernando, Sandra B. Hake, Emily Bernstein

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136 Scopus citations


Histone variants are emerging as key regulatory molecules in cancer. We report a unique 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, levels of which are also elevated in melanoma. Wefurther demonstrate that H2A.Z.2-regulated genes are bound by BRD2 and E2F1 in an H2A.Z.2-dependent manner. Importantly, H2A.Z.2 deficiency sensitizes melanoma cells to chemotherapy and targetedtherapies. 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.

Original languageEnglish
Pages (from-to)75-88
Number of pages14
JournalMolecular Cell
Issue number1
StatePublished - 2015


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