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

• 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
• Project Status: Completed (Fiscal Year 2021)
• Budget Amount: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2021: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000); Fiscal Year 2020: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000); Fiscal Year 2019: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000)
• Keywords: 遺伝子発現 / 腫瘍 / タンパク質分解 / 脂質代謝 / NRF3 / コレステロール / マクロピノサイトーシス / NRF1 / CPEB3 / 翻訳 / プロテアソーム / がん増悪 / NRF3 (NFE2L3) / 20Sプロテアソーム / ユビキチン非依存的タンパク質分解

Outline of Research at the Start

20Sと26Sプロテアソームを使い分ける生物学的な意義は未だ不明である。代表者は近年、がん増悪に関わる転写因子NRF3が、これら両方のプロテアソーム活性を制御する可能性を見出した。本課題では、このNRF3を介したユニークなプロテアソーム制御経路の解析を進めることで、他のがん研究とは異なる角度から、タンパク質恒常性の破綻によるがん増悪機構を解明する。プロテアソーム制御の異常は、がん増悪だけでなく神経変性疾患や細胞老化との関連も報告されている。そのため、本課題から得られるタンパク質恒常性の破綻機構に関する知見は、様々な疾患に対する新たな治療基盤の創出につながると期待できる。

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.

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。

Research Products

• [Journal Article] NRF3 upregulates gene expression in SREBP2-dependent mevalonate pathway with cholesterol uptake and lipogenesis inhibition (2021)
  • Author(s): Waku Tsuyoshi、Hagiwara Toru、Tamura Natsuko、Atsumi Yuri、Urano Yasuomi、Suzuki Mikiko、Iwami Takuya、Sato Katsuya、Yamamoto Masayuki、Noguchi Noriko、Kobayashi Akira
  • Journal Title: iScience Volume: 24 Issue: 10 Pages: 103180-103180
  • DOI: 10.1016/j.isci.2021.103180
  • Peer Reviewed / Open Access
• [Journal Article] Pathophysiological Potentials of NRF3-Regulated Transcriptional Axes in Protein and Lipid Homeostasis (2021)
  • Author(s): Waku Tsuyoshi、Kobayashi Akira
  • Journal Title: International Journal of Molecular Sciences Volume: 22 Issue: 23 Pages: 12686-12686
  • DOI: 10.3390/ijms222312686
  • Peer Reviewed / Open Access
• [Journal Article] NFE2L1 and NFE2L3 complementarily maintain basal proteasome activity in cancer cells through CPEB3-mediated translational repression (2020)
  • Author(s): Waku, T., Katayama, H., Hiraoka, M., Hatanaka, A., Nakamura, N., Tanaka, Y., Tamura, N., Watanabe, A., and Kobayashi, A.
  • Journal Title: Molecular and cellular biology Volume: 40 Issue: 14
  • DOI: 10.1128/mcb.00010-20
  • Peer Reviewed / Open Access
• [Journal Article] New addiction to the NRF2-related factor NRF3 in cancer cells: Ubiquitin-independent proteolysis through the 20S proteasome. (2020)
  • Author(s): Kobayashi A, Waku T.
  • Journal Title: Cancer Sci. Volume: 111 Issue: 1 Pages: 6-14
  • DOI: 10.1111/cas.14244
  • Peer Reviewed / Open Access
• [Journal Article] The inducible amphisome isolates viral hemagglutinin and defends against influenza A virus infection. (2020)
  • Author(s): Omi J, Watanabe-Takahashi M, Igai K, Shimizu E, Tseng CY, Miyasaka T, Waku T, Hama S, Nakanishi R, Goto Y, Nishino Y, Miyazawa A, Natori Y, Yamashita M, Nishikawa K.
  • Journal Title: Nat Commun. Volume: 11 Issue: 1 Pages: 162-162
  • DOI: 10.1038/s41467-019-13974-w
  • Peer Reviewed / Open Access
• [Journal Article] NRF3-POMP-20S proteasome assembly axis promotes cancer development via ubiquitin-independent proteolysis of p53 and Rb. (2020)
  • Author(s): Waku T, Nakamura N, Koji M, Watanabe H, Katoh H, Tatsumi C, Tamura N, Hatanaka A, Hirose S, Katayama H, Tani M, Kubo Y, Hamazaki J, Hamakubo T, Watanabe A, Murata S, Kobayashi A
  • Journal Title: Molecular and Cellular Biology Volume: - Issue: 10 Pages: 1-1
  • DOI: 10.1128/mcb.00597-19
  • Peer Reviewed / Open Access
• [Journal Article] β-Catenin/TCF4 Complex-Mediated Induction of the NRF3 (NFE2L3) Gene in Cancer Cells. (2019)
  • Author(s): Aono S, Hatanaka A, Hatanaka A, Gao Y, Hippo Y, Taketo MM, Waku T, Kobayashi A.
  • Journal Title: Int J Mol Sci. Volume: 20 Issue: 13 Pages: 3344-3344
  • DOI: 10.3390/ijms20133344
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] NRF1 and NRF3 complementarily maintain basal proteasome activity in cancer cells through CPEB3-Mediated translational repression (2021)
  • Author(s): 和久剛, 小林聡
  • Organizer: 第44回日本分子生物学会年会
  • Invited
• [Presentation] 転写因子NRF3はがん細胞内のセリン代謝を制御する (2020)
  • Author(s): 和久剛、廣瀬修平1、谷美里 、佐藤清敏、大澤毅、曽我朋義、小林聡
  • Organizer: 先端モデル動物プラットフォーム若手支援技術講習会
• [Presentation] Colorectal cancer addicts ubiquitin-independent 20S proteasomes assembled by the NRF3-POMP axis (2019)
  • Author(s): Tsuyoshi Waku
  • Organizer: 2019 Meeting on Ubiquitin, Autophagy & Disease (Cold Spring Harbor Laboratory Meeting)
  • Int'l Joint Research
• [Presentation] 和久剛 (2019)
  • Author(s): がん増悪性転写因子NRF3（NFE2L3）は mTORC1シグナルを活性化するアミノ酸センサーである
  • Organizer: 第9回TOR研究会
• [Presentation] NRF3-POMP経路を介したユビキチン非依存的なタンパク質分解の誘導による がん増悪メカニズム (2019)
  • Author(s): 和久剛
  • Organizer: 第7回がんと代謝研究会
• [Presentation] NRF3 (NFE2L3) contributes to colorectal cancer development through 20S proteasome assembly and the ubiquitinindependent proteolysis (2019)
  • Author(s): Tsuyoshi Waku
  • Organizer: The Environmental Response V /17th JBS Biofrontier Symposium
  • Int'l Joint Research
• [Presentation] NRF3 acts as a tumorigenic transcription factor for the assembly of a ubiquitin-independent 20S proteasome (2019)
  • Author(s): Tsuyoshi Waku
  • Organizer: 第78回日本癌学会学術総会
• [Presentation] NRF3-POMP経路を介したユビキチン非依存的なタンパク質分解の誘導によるがん増悪メカニズム (2019)
  • Author(s): 和久剛
  • Organizer: 第14回日本臨床ストレス応答学会大会
• [Remarks] 転写因子NRF3による新たな脂質代謝の 調節メカニズム解明
  • URL: https://www.doshisha.ac.jp/news/2021/1011/news-detail-8552.html