Pathophysiological role of NRF3-mediated protein degradation in colorectal cancer development

2021 Fiscal Year Final Research Report

• Project/Area Number: 19K07650
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 50010:Tumor biology-related
• Research Institution: Doshisha University
• Principal Investigator: Waku Tsuyoshi 同志社大学, 生命医科学部, 准教授 (40613584)
• Co-Investigator(Kenkyū-buntansha): 小林 聡 同志社大学, 生命医科学部, 教授 (50292214)
• Project Period (FY): 2019-04-01 – 2022-03-31
• Keywords: 遺伝子発現 / 腫瘍 / タンパク質分解 / 脂質代謝

Outline of Final Research Achievements

The mechanism of how proteasome activity is maintained in cancer cells has remained unclear. The transcription factor NRF1 induces the expression of almost all proteasome-related genes under proteasome inhibition. NRF1 and its phylogenetically closest homolog NRF3 are both highly expressed in several types of cancers, such as colorectal cancer. Herein, we provide the novel regulatory mechanism of basal proteasome activity in cancer cells through an NRF3-CPEB3-NRF1 translational repression axis.
The genetic association of a transcription factor NRF3 with obesity has been suggested, although the molecular mechanisms remain unknown. Here, we found that NRF3 up-regulated gene expression in the SREBP2-dependent mevalonate pathway by inducing the gene expression and forming a transcriptional complex. NRF3 also induced macropinocytosis for cholesterol uptake and GGPP production for lipogenesis inhibition. This study provides the gene expression network of NRF3-regulated lipid metabolism.

Free Research Field

遺伝子発現

Academic Significance and Societal Importance of the Research Achievements

本研究が解明したNRF3-CPEB3-NRF1経路を標的とすることで、がん細胞に特異的に作用するタンパク質分解のコンロトールを目的とした新たな抗がん剤開発につながると期待できる。また本研究ではNRF3がコレステロール生合成を調節することで中性脂肪量を減少させることも見出した。以上の知見は、NRF3が肥満とがん悪性化をつなぐキーファクターである可能性を強く示している。肥満はがん増悪の原因となることが知られているが不明な点も多いことから、本研究で得られた知見は肥満とがんの関連を理解する上で重要なものであると考えられる。