H2AT120 Phosphorylation by VPRBP Silences Tumor Suppressor Genes

Vpr binding protein (VPRBP) was initially identified as a binding partner of HIV viral protein R and is thought to act as a substrate-targeting subunit of an E3 ubiquitin ligase complex. Recent studies have suggested that VPRBP may establish transcriptionally silent chromatin, but the underlying mechanism is unknown. Kim and colleagues observed that VPRBP was overexpressed in prostate, bladder, and breast cancer cell lines and specifically associated with increased histone H2A threonine 120 (H2AT120) phosphorylation. Recombinant VPRBP phosphorylated free and nucleosomal H2A in vitro, and mutation of H2AT120 abolished VPRBP-mediated phosphorylation, indicating that VPRBP has intrinsic kinase activity toward H2AT120. VPRBP and phospho-H2AT120 levels were increased in over 70% of primary tumor samples compared with matched normal tissue, particularly in bladder, breast, and prostate cancers, suggesting that VPRBP-dependent H2AT120 phosphorylation may be oncogenic. Consistent with this possibility, knockdown of VPRBP decreased H2AT120 phosphorylation and significantly impaired proliferation and colony formation of a bladder cancer cell line. Phosphorylation of H2AT120 by VPRBP inhibited transcription in vitro, and chromatin immunoprecipitation experiments showed that VPRBP directly regulated H2AT120 phosphorylation at target gene promoters. Of note, genes upregulated upon VPRBP knockdown in bladder cancer cells were enriched for regulators of cell growth and proliferation, some of which have been implicated as tumor suppressor genes. A VPRBP-selective inhibitor identified in a compound library screen was well tolerated in mice and significantly inhibited growth of bladder cancer cells in vivo in association with markedly reduced H2AT120 levels at the promoters of VPRBP target genes. Although studies in additional tumor types with more potent inhibitors are warranted, these findings suggest that VPRBP promotes gene silencing and cancer cell proliferation through H2AT120 phosphorylation and may represent a potential therapeutic target.

Kim K, Kim JM, Kim JS, Choi J, Lee YS, Neamati N, et al. VprBP has intrinsic kinase activity targeting histone H2A and represses gene transcription. Mol Cell 2013;52:459–67.

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