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Programmed cell death 5 mediates HDAC3 decay to promote genotoxic stress response

Author

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  • Hyo-Kyoung Choi

    (Brain Korea 21 PLUS Project for Medical Sciences, Yonsei University College of Medicine)

  • Youngsok Choi

    (CHA University)

  • Eun Sung Park

    (Medical Convergence Research Institute, Yonsei University College of Medicine)

  • Soo-Yeon Park

    (Brain Korea 21 PLUS Project for Medical Sciences, Yonsei University College of Medicine)

  • Seung-Hyun Lee

    (Brain Korea 21 PLUS Project for Medical Sciences, Yonsei University College of Medicine)

  • Jaesung Seo

    (Brain Korea 21 PLUS Project for Medical Sciences, Yonsei University College of Medicine)

  • Mi-Hyeon Jeong

    (Brain Korea 21 PLUS Project for Medical Sciences, Yonsei University College of Medicine)

  • Jae-Wook Jeong

    (Gynecology and Reproductive Biology, Michigan State University College of Human Medicine)

  • Jae-Ho Cheong

    (Yonsei University College of Medicine)

  • Peter C. W. Lee

    (University of Ulsan College of Medicine)

  • Kyung-Chul Choi

    (University of Ulsan College of Medicine)

  • Ho-Geun Yoon

    (Brain Korea 21 PLUS Project for Medical Sciences, Yonsei University College of Medicine)

Abstract

The inhibition of p53 activity by histone deacetylase 3 (HDAC3) has been reported, but the precise molecular mechanism is unknown. Here we show that programmed cell death 5 (PDCD5) selectively mediates HDAC3 dissociation from p53, which induces HDAC3 cleavage and ubiquitin-dependent proteasomal degradation. Casein kinase 2 alpha phosphorylates PDCD5 at Ser-119 to enhance its stability and importin 13-mediated nuclear translocation of PDCD5. Genetic deletion of PDCD5 abrogates etoposide (ET)-induced p53 stabilization and HDAC3 cleavage, indicating an essential role of PDCD5 in p53 activation. Restoration of PDCD5WT in PDCD5−/− MEFs restores ET-induced HDAC3 cleavage. Reduction of both PDCD5 and p53, but not reduction of either protein alone, significantly enhances in vivo tumorigenicity of AGS gastric cancer cells and correlates with poor prognosis in gastric cancer patients. Our results define a mechanism for p53 activation via PDCD5-dependent HDAC3 decay under genotoxic stress conditions.

Suggested Citation

  • Hyo-Kyoung Choi & Youngsok Choi & Eun Sung Park & Soo-Yeon Park & Seung-Hyun Lee & Jaesung Seo & Mi-Hyeon Jeong & Jae-Wook Jeong & Jae-Ho Cheong & Peter C. W. Lee & Kyung-Chul Choi & Ho-Geun Yoon, 2015. "Programmed cell death 5 mediates HDAC3 decay to promote genotoxic stress response," Nature Communications, Nature, vol. 6(1), pages 1-18, November.
    • Handle: RePEc:nat:natcom:v:6:y:2015:i:1:d:10.1038_ncomms8390
    DOI: 10.1038/ncomms8390
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