Histone deacetylase inhibitors valproic acid and depsipeptide sensitize retinoblastoma cells to radiotherapy by increasing H2AX phosphorylation and p53 acetylation-phosphorylation

  • Authors:
    • Takeshi Kawano
    • Masaharu Akiyama
    • Miyuki Agawa-Ohta
    • Yoko Mikami-Terao
    • Satsuki Iwase
    • Takaaki Yanagisawa
    • Hiroyuki Ida
    • Naoki Agata
    • Hisashi Yamada
  • View Affiliations

  • Published online on: October 1, 2010     https://doi.org/10.3892/ijo_00000728
  • Pages: 787-795
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Abstract

Although p53 is intact in most cases of retinoblastoma, it is largely inactivated by the ubiqutin-proteasome system through interaction with murine double minute 2 (MDM2) and murine double minute X (MDMX). The present study showed that the histone deacetylase (HDAC) inhibitors valproic acid (VPA) and depsipeptide (FK228) synergistically enhanced ionizing radiation (IR)-induced apoptosis, associated with activation of caspase-3 and cleavage of poly(ADP-ribose) polymerase in Y79 and WER1-Rb1 human retinoblastoma cells. Both VPA and FK228 enhanced IR-induced phosphorylation of histone H2AX on Ser139 preceding apoptosis. Exposure of cells to IR in the presence of VPA or FK228 induced the accumulation of p53 acetylated at Lys382 and phosphorylated at Ser46 through the reduction of binding affinity with MDM2 and MDMX. These results suggest that acetylation of p53 by HDAC inhibitors is a promising new therapeutic target in refractory retinoblastoma.

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October 2010
Volume 37 Issue 4

Print ISSN: 1019-6439
Online ISSN:1791-2423

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Spandidos Publications style
Kawano T, Akiyama M, Agawa-Ohta M, Mikami-Terao Y, Iwase S, Yanagisawa T, Ida H, Agata N and Yamada H: Histone deacetylase inhibitors valproic acid and depsipeptide sensitize retinoblastoma cells to radiotherapy by increasing H2AX phosphorylation and p53 acetylation-phosphorylation. Int J Oncol 37: 787-795, 2010
APA
Kawano, T., Akiyama, M., Agawa-Ohta, M., Mikami-Terao, Y., Iwase, S., Yanagisawa, T. ... Yamada, H. (2010). Histone deacetylase inhibitors valproic acid and depsipeptide sensitize retinoblastoma cells to radiotherapy by increasing H2AX phosphorylation and p53 acetylation-phosphorylation. International Journal of Oncology, 37, 787-795. https://doi.org/10.3892/ijo_00000728
MLA
Kawano, T., Akiyama, M., Agawa-Ohta, M., Mikami-Terao, Y., Iwase, S., Yanagisawa, T., Ida, H., Agata, N., Yamada, H."Histone deacetylase inhibitors valproic acid and depsipeptide sensitize retinoblastoma cells to radiotherapy by increasing H2AX phosphorylation and p53 acetylation-phosphorylation". International Journal of Oncology 37.4 (2010): 787-795.
Chicago
Kawano, T., Akiyama, M., Agawa-Ohta, M., Mikami-Terao, Y., Iwase, S., Yanagisawa, T., Ida, H., Agata, N., Yamada, H."Histone deacetylase inhibitors valproic acid and depsipeptide sensitize retinoblastoma cells to radiotherapy by increasing H2AX phosphorylation and p53 acetylation-phosphorylation". International Journal of Oncology 37, no. 4 (2010): 787-795. https://doi.org/10.3892/ijo_00000728