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PPM1A is a RelA phosphatase with tumor suppressor-like activity

Oncogene volume 33, pages 2918–2927 (2014)Cite this article

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Abstract

Nuclear factor-κB (NF-κB) signaling contributes to human disease processes, notably inflammatory diseases and cancer. NF-κB has a role in tumorigenesis and tumor growth, as well as promotion of metastases. Mechanisms responsible for abnormal NF-κB activation are not fully elucidated; however, RelA phosphorylation, particularly at serine residues S536 and S276, is critical for RelA function. Kinases that phosphorylate RelA promote oncogenic behaviors, suggesting that phosphatases targeting RelA could have tumor-inhibiting activities; however, few RelA phosphatases have been identified. Here, we identified tumor inhibitory and RelA phosphatase activities of the protein phosphatase 2C (PP2C) phosphatase family member, PPM1A. We show that PPM1A directly dephosphorylated RelA at residues S536 and S276 and selectively inhibited NF-κB transcriptional activity, resulting in decreased expression of monocyte chemotactic protein-1/chemokine (C–C motif) ligand 2 and interleukin-6, cytokines implicated in cancer metastasis. PPM1A depletion enhanced NF-κB-dependent cell invasion, whereas PPM1A expression inhibited invasion. Analyses of human expression data revealed that metastatic prostate cancer deposits had lower PPM1A expression compared with primary tumors without distant metastases. A hematogenous metastasis mouse model revealed that PPM1A expression inhibited bony metastases of prostate cancer cells after vascular injection. In summary, our findings suggest that PPM1A is a RelA phosphatase that regulates NF-κB activity and that PPM1A has tumor suppressor-like activity. Our analyses also suggest that PPM1A inhibits prostate cancer metastases and as neither gene deletions nor inactivating mutations of PPM1A have been described, increasing PPM1A activity in tumors represents a potential therapeutic strategy to inhibit NF-κB signaling or bony metastases in human cancer.

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Acknowledgements

We thank W Sun, LA Donehower, N Perkins, Reuven Agami and IM Verma for providing constructs and cell lines. We are extremely grateful to A Richmond, R Matusik, J McLean, A Weaver, D Webb and to Baker Lab members for insightful advice. This work was supported by Grant NIH R01 DE013173 (to WGY) and by funds provided through an endowment from Barry and Amy Baker to the Barry Baker Laboratory for Head & Neck Oncology, from the Vanderbilt Ingram Cancer Center, from the Department of Otolaryngology at Vanderbilt University and from the Vanderbilt Bill Wilkerson Center.

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Authors and Affiliations

  1. Department of Cancer Biology, Vanderbilt University, Nashville, TN, USA

    X Lu, H An & Y Guo

  2. Division of Surgical Sciences, Vanderbilt University, Nashville, TN, USA

    H An

  3. Vanderbilt Prostate Cancer Center, Vanderbilt University, Nashville, TN, USA

    R Jin

  4. Department of Urology, Vanderbilt University, Nashville, TN, USA

    R Jin

  5. Division of Otolaryngology, Department of Surgery, Yale University, New Haven, CT, USA

    M Zou, D Liu & W G Yarbrough

  6. Department of Biostatistics, Vanderbilt University, Nashville, TN, USA

    P-F Su & Y Shyr

  7. Department of Pathology, Yale University, New Haven, CT, USA

    W G Yarbrough

  8. Yale Cancer Center, New Haven, CT, USA

    W G Yarbrough

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Lu, X., An, H., Jin, R. et al. PPM1A is a RelA phosphatase with tumor suppressor-like activity. Oncogene 33, 2918–2927 (2014). https://doi.org/10.1038/onc.2013.246

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