Regulation of energy metabolism involved in EMT and cell invasion of endometrial cancer cells

2023 Fiscal Year Final Research Report

• Project/Area Number: 21K09519
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 56040:Obstetrics and gynecology-related
• Research Institution: Kyushu University
• Principal Investigator: ASANOMA KAZUO 九州大学, 医学研究院, 准教授 (30380413)
• Project Period (FY): 2021-04-01 – 2024-03-31
• Keywords: 子宮体癌 / 解糖系 / 酸化的リン酸化 / エネルギー代謝 / 転写調節 / 脱リン酸化酵素

Outline of Final Research Achievements

BHLHE40 is a transcription factor that is involved in multiple cell activities. In this study, we found that BHLHE40 expression was downregulated in cases of endometrial cancer of higher grade and advanced disease. Knockdown of BHLHE40 in endometrial cancer cells resulted in suppressed oxygen consumption and enhanced extracellular acidification. Suppressed PDH activity and enhanced LDH activity was observed in the knockdown cells. Knockdown of BHLHE40 also led to dephosphorylation of AMPKα Thr172 and enhanced phosphorylation of PDH E1 subunit alpha 1 (PDHA1) Ser293 and LDHA Tyr10. These results suggested that BHLHE40 modulates PDH and LDH activity by regulating the phosphorylation status of PDHA1 and LDHA. We found that BHLHE40 enhanced AMPKα phosphorylation by directly suppressing PPM1F. Our immunohistochemical study showed that the expression of BHLHE40, PPM1F, and phosphorylated AMPKα correlated with the prognosis of endometrial cancer patients.

Free Research Field

婦人科腫瘍学

Academic Significance and Societal Importance of the Research Achievements

我々はBHLHE40-PPM1F-AMPKの経路が解糖系と酸化的リン酸化を制御することにより細胞内のエネルギー調節を司り、子宮体癌の進展を制御していることが示唆された。これらの結果はBHLHE40、PPM1F、リン酸化AMPKαが予後マーカーとして利用できる可能性を提示し、また、BHLHE40-PPM1F-AMPK経路を標的とした分子治療の可能性を提示するものである。