Envolvement of abnormal of SETDB-related histone modification enzyme and tumor immune environment in gastrointestinal cancer

2022 Fiscal Year Final Research Report

• Project/Area Number: 20H03526
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Review Section: Basic Section 50020:Tumor diagnostics and therapeutics-related
• Research Institution: Tokyo Medical and Dental University
• Principal Investigator: Akiyama Yoshimitsu 東京医科歯科大学, 大学院医歯学総合研究科, 講師 (80262187)
• Co-Investigator(Kenkyū-buntansha): 新部 彩乃 (樺嶋彩乃) 東京医科歯科大学, 大学院医歯学総合研究科, 助教 (20445448) ; 島田 周 東京医科歯科大学, 大学院医歯学総合研究科, 助教 (20609705) ; 田中 真二 東京医科歯科大学, 大学院医歯学総合研究科, 教授 (30253420)
• Project Period (FY): 2020-04-01 – 2023-03-31
• Keywords: エピジェネティクス / エピゲノム / ヒストン修飾 / SETDB1 / SETDB2 / H3K9me3 / 難治性消化器癌 / 腫瘍免疫

Outline of Final Research Achievements

We examined the molecular functions of histone H3K9 trimethyltransferases, SETDB1/2, in refractory gastrointestinal cancers. SETDB1 is highly expressed in approximately 40% of gastric and liver cancers, which was associated with worse prognosis. Overexpression and knockdown of SETDB1 and SETDB2 in gastric cancer cells showed that both genes were associated with increased cell proliferation and invasiveness. Moreover, Setdb1-overexpressed mice gastric cells were able to grow after subcutaneously transplanted into syngeneic mice, suggesting an immune evasion. The expression of tumor-related genes and immune-related factors was altered in gastric and liver cancer cells with SETDB1 overexpression or knockdown. In addition, SETDB1 binds to many proteins with cancer-promoting functions, such as RNA modifiers and other histone modification proteins. Our findings indicate that SETDB1 complexes may be new therapeutic targets.

Free Research Field

分子腫瘍学

Academic Significance and Societal Importance of the Research Achievements

SETDB型ヒストメチル化酵素は多くの悪性腫瘍で発現亢進し、癌の悪性度や予後に関連するが、有効な治療法は未だに確立されていない。本研究では胃癌と肝癌のSETDB1高発現の機能的役割が明らかとなった。更にSETDB1によって発現調節される癌関連遺伝子や免疫関連遺伝子群が同定され、SETDB1による癌促進機能および腫瘍免疫の関連が示唆された。SETDB1複合体因子の同定にも成功し、これら複合体因子を標的とした癌診断およびエピジェネティック創薬開発への発展が期待できる。