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

2019 Fiscal Year Final Research Report

• Project/Area Number: 17K00565
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Risk sciences of radiation and chemicals
• Research Institution: National Institutes for Quantum and Radiological Science and Technology
• Principal Investigator: Nakajima Nakako 国立研究開発法人量子科学技術研究開発機構, 放射線医学総合研究所 重粒子線治療研究部, 研究員(任常) (50402863)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Keywords: 放射線治療 / DNA損傷 / 腫瘍免疫 / エピジェネティクス

Outline of Final Research Achievements

The upregulation of major histocompatibility complex class I-related chain A and B (MICA/B) 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 this study, 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. 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.

Free Research Field

放射線医学

Academic Significance and Societal Importance of the Research Achievements

免疫療法の奏功率は２割程度であり、免疫監視機構からの腫瘍のエスケープが免疫療法の奏功を妨げる原因の一つとなっている。腫瘍細胞上に発現するMICAは腫瘍免疫を活性化する分子であるが、腫瘍によってはMICA低発現細胞が存在する。本研究の結果から、放射線応答とヒストン修飾酵素阻害剤によって、低発現細胞のMICA発現を回復できることが明らかになった。このことは放射線治療とヒストン修飾酵素阻害剤の併用による新たな免疫療法を開発するための基盤となり得る。