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Inhibition of the HDAC/Suv39/G9a pathway restores the expression of DNA damage-dependent major histocompatibility complex class I-related chain A and B in cancer cells

  • Authors:
    • Nakako Izumi Nakajima
    • Atsuko Niimi
    • Mayu Isono
    • Takahiro Oike
    • Hiro Sato
    • Takashi Nakano
    • Atsushi Shibata
  • View Affiliations / Copyright

    Affiliations: Radiological Science Research and Development Directorate, National Institutes for Quantum and Radiological Science and Technology, Chiba 263-8555, Japan, Research Program for Heavy Ion Therapy, Division of Integrated Oncology Research, Gunma University Initiative for Advanced Research, Maebashi, Gunma 371-8511, Japan, Advanced Scientific Research Leaders Development Unit, Gunma University, Maebashi, Gunma 371-8511, Japan, Department of Radiation Oncology, Gunma University, Maebashi, Gunma 371-8511, Japan
    Copyright: © Nakajima et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
  • Pages: 693-702
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    Published online on: June 30, 2017
       https://doi.org/10.3892/or.2017.5773
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Abstract

Immunotherapy is expected to be promising as a next generation cancer therapy. Immunoreceptors are often activated constitutively in cancer cells, however, such levels of ligand expression are not effectively recognized by the native immune system due to tumor microenvironmental adaptation. Studies have demonstrated that natural-killer group 2, member D (NKG2D), a major activating immunoreceptor, responds to DNA damage. The upregulation of major histocompatibility complex class I-related chain A and B (MICA/B) (members of NKG2D ligands) expression after DNA damage is associated with NK cell-mediated killing of cancer cells. However, the regulation of DNA damage-induced MICA/B expression has not been fully elucidated in the context of the types of cancer cell lines. In the present study, we found that MICA/B expression varied between cancer cell lines after DNA damage. Screening in terms of chromatin remodeling identified that inhibitors related to chromatin relaxation via post-translational modification on histone H3K9, i.e. HDAC, Suv39 or G9a inhibition, restored DNA damage-dependent MICA/B expression in insensitive cells. In addition, we revealed that the restored MICA/B expression was dependent on ATR as well as E2F1, a transcription factor. We further revealed that low‑dose treatment of an HDAC inhibitor was sufficient to restore MICA/B expression in insensitive cells. Finally, we demonstrated that HDAC inhibition restored DNA damage‑dependent cytotoxic NK activity against insensitive cells. Thus, the present study revealed that DNA damage‑dependent MICA/B expression in insensitive cancer cells can be restored by chromatin relaxation via the HDAC/Suv39/G9a pathway. Collectively, manipulation of chromatin status by therapeutic cancer drugs may potentiate the antitumor effect by enhancing immune activation following radiotherapy and DNA damage-associated chemotherapy.
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Copy and paste a formatted citation
Spandidos Publications style
Nakajima NI, Niimi A, Isono M, Oike T, Sato H, Nakano T and Shibata A: Inhibition of the HDAC/Suv39/G9a pathway restores the expression of DNA damage-dependent major histocompatibility complex class I-related chain A and B in cancer cells. Oncol Rep 38: 693-702, 2017.
APA
Nakajima, N.I., Niimi, A., Isono, M., Oike, T., Sato, H., Nakano, T., & Shibata, A. (2017). Inhibition of the HDAC/Suv39/G9a pathway restores the expression of DNA damage-dependent major histocompatibility complex class I-related chain A and B in cancer cells. Oncology Reports, 38, 693-702. https://doi.org/10.3892/or.2017.5773
MLA
Nakajima, N. I., Niimi, A., Isono, M., Oike, T., Sato, H., Nakano, T., Shibata, A."Inhibition of the HDAC/Suv39/G9a pathway restores the expression of DNA damage-dependent major histocompatibility complex class I-related chain A and B in cancer cells". Oncology Reports 38.2 (2017): 693-702.
Chicago
Nakajima, N. I., Niimi, A., Isono, M., Oike, T., Sato, H., Nakano, T., Shibata, A."Inhibition of the HDAC/Suv39/G9a pathway restores the expression of DNA damage-dependent major histocompatibility complex class I-related chain A and B in cancer cells". Oncology Reports 38, no. 2 (2017): 693-702. https://doi.org/10.3892/or.2017.5773
Copy and paste a formatted citation
x
Spandidos Publications style
Nakajima NI, Niimi A, Isono M, Oike T, Sato H, Nakano T and Shibata A: Inhibition of the HDAC/Suv39/G9a pathway restores the expression of DNA damage-dependent major histocompatibility complex class I-related chain A and B in cancer cells. Oncol Rep 38: 693-702, 2017.
APA
Nakajima, N.I., Niimi, A., Isono, M., Oike, T., Sato, H., Nakano, T., & Shibata, A. (2017). Inhibition of the HDAC/Suv39/G9a pathway restores the expression of DNA damage-dependent major histocompatibility complex class I-related chain A and B in cancer cells. Oncology Reports, 38, 693-702. https://doi.org/10.3892/or.2017.5773
MLA
Nakajima, N. I., Niimi, A., Isono, M., Oike, T., Sato, H., Nakano, T., Shibata, A."Inhibition of the HDAC/Suv39/G9a pathway restores the expression of DNA damage-dependent major histocompatibility complex class I-related chain A and B in cancer cells". Oncology Reports 38.2 (2017): 693-702.
Chicago
Nakajima, N. I., Niimi, A., Isono, M., Oike, T., Sato, H., Nakano, T., Shibata, A."Inhibition of the HDAC/Suv39/G9a pathway restores the expression of DNA damage-dependent major histocompatibility complex class I-related chain A and B in cancer cells". Oncology Reports 38, no. 2 (2017): 693-702. https://doi.org/10.3892/or.2017.5773
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