Phosphorylation of Histone H2A Promotes Tumorigenesis

Several histone-modifying enzymes and specific histone modifications have been linked to cancer, but the underlying tumor-promoting mechanisms are less clear. Aihara, Nakagawa, Mizusaki, and colleagues found that some cancer cell lines exhibited hyperphosphorylation of histone H2A at T120. In Drosophila the NHK1 kinase specifically phosphorylates H2A, and, accordingly, the human homolog, VRK1, was found to phosphorylate H2A at T120 (H2A pT120) in human cancer cells. Depletion of VRK1 in cancer cells with hyperphosphorylated H2A T120 downregulated the oncogenic cell-cycle regulator CCND1 (encoding cyclin D1) and suppressed cell growth. Chromatin immunoprecipitation sequencing (ChIP-seq) revealed overlap between VRK1 and H2A pT120 peaks especially at transcription start sites (TSS), including the TSS of CCND1. Further, when VRK1 was depleted, H2A pT120 was largely absent at the CCND1 locus and CCND1 expression was reduced, indicating that VRK1 promotes CCND1 expression via phosphorylation of H2A at the CCND1 TSS. In contrast, ubiquitination of H2A at K119 (H2A ubK119) was largely mutually exclusive with H2A pT120 and was associated with transcriptional repression, whereas H2A pT120 was associated with transcriptionally active chromatin. H2A ubK119 prevented phosphorylation of H2A pT120, and also prevented methylation of H3K4, which is essential for transcriptional activation. Conversely, an H2A phosphomimetic (T120D) reduced H2A ubiquitination, indicating that antagonism between H2A ubiquitination and phosphorylation regulates transcriptional activation. Moreover, H2A T120D enhanced colony formation and proliferation in vitro, and promoted growth of tumor xenografts in vivo, establishing H2A pT120 as an oncogenic histone modification. Although VRK1, which also enhanced the growth of tumor xenografts when overexpressed, has been reported to be involved in the DNA damage response, expression of H2A T120D did not enhance genomic instability, suggesting that H2A pT120 promotes oncogenesis by an epigenetic mechanism. Collectively, these findings identify a potential role for H2A T120 phosphorylation in oncogenesis and implicate VRK1 in the epigenetic regulation of CCND1 and other genes.

Aihara H, Nakagawa T, Mizusaki H, Yoneda M, Kato M, Doiguchi M, et al. Histone H2A T120 phosphorylation promotes oncogenic transformation via upregulation of cyclin D1. Mol Cell 2016;64:176–88.