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Phosphorylation of histone H3 serine 28 modulates RNA polymerase III-dependent transcription

Oncogene volume 30, pages 3943–3952 (2011)Cite this article

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Abstract

Deregulation of RNA polymerase III (Pol III) transcription enhances cellular tRNAs and 5S rRNA production, leading to an increase in translational capacity to promote cell proliferation, transformation and tumor formation. Phosphorylation of histone H3 (H3ph) is induced by tumor promoters (EGF, UV and TPA) and immediate early genes, such as c-myc, c-jun and c-fos. However, it remains to be determined whether H3ph is involved in RNA Pol III transcription. Here, we report that EGF strongly induced H3ph at serine 28 (H3S28ph). EGF significantly increased transcription of RNA Pol III-dependent genes (Pol III genes), tRNALeu, tRNATyr, 5S rRNA and 7SL RNA. Inhibition of EGFR, but not PI3K, reduced both H3S28ph and tRNALeu and 5S rRNA transcription. EGF enhanced occupancy of H3S28ph in the promoters of tRNALeu and 5S rRNA. Further analysis indicates that EGF augmented cellular levels of protein and mRNA of TFIIIB subunits, Brf1 and TATA box-binding protein (TBP). Brf1 is a specific transcription factor for RNA Pol III genes. EGF enhanced occupancy of H3S28ph in the Brf1 and TBP promoters. Inhibition of H3S28ph by mutant H3S28A repressed Brf1, TBP and tRNALeu and 5S rRNA expression and decreased occupancy of H3S28ph in their promoters. Reduction of Brf1 significantly decreased tRNALeu and 5S rRNA transcription and repressed EGF-induced anchorage-independent growth. Blocking H3S28ph signaling by using mutant H3S28A reduced EGF-induced cell transformation. Together, these results indicate that EGF activates EGFR signaling to induce H3S28ph, which, in turn, upregulates tRNALeu and 5S rRNA transcription through Brf1 and TBP and promotes cell transformation. The studies demonstrate that epigenetic modification of H3S28ph has a critical role in the activity of Pol III genes.

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Acknowledgements

We want to thank DL, Johnson and MR Stallcup (University of Southern California) for scientific discussions. We would like to thank Z Dong (University of Minnesota) and C Huang (University of New York) who provided cell lines. This work was supported by National Institutes of Health grants AA017288 to SZ and DK025836-26 to DL.

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Authors and Affiliations

  1. Department of Biochemistry and Molecular Biology, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA

    Q Zhang, Q Zhong, A G Evans, D Levy & S Zhong

  2. Department of Medical Oncology, Jinling Hospital, Nanjing, Jiangsu, China

    Q Zhang

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  1. Q Zhang
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Correspondence to S Zhong.

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Zhang, Q., Zhong, Q., Evans, A. et al. Phosphorylation of histone H3 serine 28 modulates RNA polymerase III-dependent transcription. Oncogene 30, 3943–3952 (2011). https://doi.org/10.1038/onc.2011.105

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