Respiratory complex I-mediated cancer cell proliferation control via histone modification and its clinical significance

2023 Fiscal Year Final Research Report

• Project/Area Number: 22K15516
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 50010:Tumor biology-related
• Research Institution: Showa University
• Principal Investigator: Higurashi Masato 昭和大学, 薬学部, 助教 (50882487)
• Project Period (FY): 2022-04-01 – 2024-03-31
• Keywords: ミトコンドリア / 呼吸鎖複合体I / NAD+ / SIRT3 / SIRT7 / p21Cip1

Outline of Final Research Achievements

In this study, I found that inhibition of NADH dehydrogenase activity in respiratory chain complex I induces expression of p21Cip1, accompanying a decrease in NAD+ levels within cells. The decrease in the NAD+ increased acetylation of H3K18 in the region proximal to p21Cip1 promoter by downregulation of SIRT7. Furthermore, a reduction in NAD+ levels result in a decline in SIRT3 activity, which increased p21Cip1 expression at the translational level. These findings suggest that cancer cells maintain their proliferative potential by suppressing 21Cip1 expression by regenerating NAD+ through respiratory chain complex I activity. Importantly, high expression levels of complex I core subunits correlated with poor prognosis in patients with the hormone receptor (+)/HER2(-) subtype of breast cancer. Therefore, NADH dehydrogenase and SIRT3/7 have emerged as promising therapeutic targets against the breast cancer subtype.

Free Research Field

腫瘍細胞生物学

Academic Significance and Societal Importance of the Research Achievements

癌細胞の代謝は一般に解糖系に依存しているが、一方で、本研究の成果によると、呼吸鎖複合体ⅠによるNADHからのNAD+の再生が十分に行われないと、SIRT3/SIRT7の活性が低下して翻訳/転写レベルでp21Cip1が誘導され、癌細胞は増殖できなくなる。従って、呼吸鎖活性も癌細胞の増殖能維持に必須である。実際、複合体Ⅰの構成サブユニットの高発現はLuminal型乳癌の予後不良因子であった。従って、呼吸鎖複合体Ⅰ活性を標的とする癌治療はLuminal型乳癌に有望なアプローチとなることが期待できる。