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Coordination of PAD4 and HDAC2 in the regulation of p53-target gene expression

Oncogene volume 29, pages 3153–3162 (2010)Cite this article

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Abstract

Histone Arg methylation and Lys acetylation have been found to cooperatively regulate the expression of p53-target genes. Peptidylarginine deiminase 4 (PAD4) is an enzyme that citrullinates histone arginine and monomethyl-arginine residues thereby regulating histone Arg methylation. We have recently found that PAD4 serves as a p53 corepressor to regulate histone Arg methylation at the p53-target gene p21/WAF1/CIP1 promoter. However, it has not been tested whether histone Arg citrullination coordinates with other histone modifications to repress transcription. Here, we show that histone deacetylase (HDAC2) and PAD4 interact with p53 through distinct domains and simultaneously associate with the p21 promoter to regulate gene expression. After DNA damage, PAD4 and HDAC2 dissociate from several p53-target gene promoters (for example, p21, GADD45, and PUMA) with a concomitant increase in histone Lys acetylation and Arg methylation at these promoters. Furthermore, PAD4 promoter association and histone Arg modifications are regulated by p53 and HDAC activity. In contrast, HDAC2 promoter association and histone Lys acetylation are affected by p53 and PAD4 activity at minor degrees. Importantly, PAD4 inhibitor Cl-amidine and HDAC inhibitor suberoylanilide hydroxamic acid show additive effects in inducing p21, GADD45, and PUMA expression and inhibiting cancer cell growth in a p53-dependent manner. Our results unveil an important crosstalk between histone deacetylation and citrullination, suggesting that a combination of PAD4 and HDAC2 inhibitors as a potential strategy for cancer treatment.

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Acknowledgements

We are grateful to Drs JC Reese, DS Gilmour, BF Pugh, and S Tan for discussions and helpful comments. Research is supported in part by a PSU start-up fund and NIH Grants R01 CA136856 to YW (PSU) and R01 CA116522 to YW (UC Riverside).

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Author notes

  1. H Yao: Laboratory of Molecular Biology, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892, USA.

Authors and Affiliations

  1. Department of Biochemistry and Molecular Biology, Center for Eukaryotic Gene Regulation, Pennsylvania State University, University Park, PA, USA

    P Li, D Wang, H Yao, P Doret, Q Shen & Y Wang

  2. Department of Pharmacology, Weill Medical College of Cornell University, New York, NY, USA

    G Hao

  3. Department of Chemistry-027, University of California, Riverside, CA, USA

    H Qiu & Y Wang

  4. Department of Pathology and Cell Biology, University of South Florida College of Medicine, Tampa, FL, USA

    X Zhang

  5. Department of Chemistry, Pennsylvania State University,

    G Chen

  6. University Park, PA, USA

    G Chen

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  1. P Li
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Correspondence to Y Wang.

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Li, P., Wang, D., Yao, H. et al. Coordination of PAD4 and HDAC2 in the regulation of p53-target gene expression. Oncogene 29, 3153–3162 (2010). https://doi.org/10.1038/onc.2010.51

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