The role of autophagy in the maintenance of genomic stability and tumor suppression

• Project/Area Number: 19H03454
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Review Section: Basic Section 49030:Experimental pathology-related
• Research Institution: Nagasaki University
• Principal Investigator: Kawabata Tsuyoshi 長崎大学, 原爆後障害医療研究所, 助教 (60734580)
• Co-Investigator(Kenkyū-buntansha): 安井 孝周 名古屋市立大学, 医薬学総合研究院(医学), 教授 (40326153) ; 海野 怜 名古屋市立大学, 医薬学総合研究院(医学), 研究員 (40755683)
• Project Period (FY): 2019-04-01 – 2022-03-31
• Project Status: Completed (Fiscal Year 2021)
• Budget Amount: ¥17,290,000 (Direct Cost: ¥13,300,000、Indirect Cost: ¥3,990,000); Fiscal Year 2021: ¥5,850,000 (Direct Cost: ¥4,500,000、Indirect Cost: ¥1,350,000); Fiscal Year 2020: ¥5,460,000 (Direct Cost: ¥4,200,000、Indirect Cost: ¥1,260,000); Fiscal Year 2019: ¥5,980,000 (Direct Cost: ¥4,600,000、Indirect Cost: ¥1,380,000)
• Keywords: オートファジー / ゲノム安定性の維持 / 複製ストレス / 発がん / ファンコニ経路 / エピジェネティクス / ゲノム安定性 / がん抑制遺伝子 / がん / ゲノム情報の維持

Outline of Research at the Start

オートファジーはオートファゴソームと呼ばれる構造が細胞内の一部を包み込んで分解する機構である。この働きにより細胞内の不要物が恒常的に分解され、細胞・組織の恒常性が維持される。オートファジーは結果として様々な疾患を抑制し、発がんも防ぐ事が分かっているが、そのメカニズムの全貌は未だ明らかとなっていない。本研究では、オートファジーがゲノム情報を安定に維持するメカニズムを解明し、オートファジーの異常からがん抑制遺伝子の機能破綻、さらに発がんへと至る道筋を示す。

Outline of Final Research Achievements

Autophagy maintains tissue homeostasis and prevents carcinogenesis. In this study, we show that disruption of autophagy leads to dysfunction of the Fanconi anemia pathway and genomic instability associated with replication stress. In autophagy-deficient cells, the expression of the FA protein FANCF was decreased due to epigenetic changes. Comprehensive genome-wide analysis revealed that autophagy deficiency induces copy-number variations in genomic regions encoding multiple cancer-suppressor genes, and results in decreased expression of these genes. This indicates that autophagy deficiency causes genetic and epigenetic abnormalities due to defects in the FA pathway, leading to loss of function of other tumor suppressors and promotion of early tumorigenesis. This study proposes a mechanism by which cancer cells arise from normal cells via abnormalities in autophagy, contributing to develop applications to new cancer prevention and treatment.

Academic Significance and Societal Importance of the Research Achievements

オートファジーは様々な疾患を予防する生体防御機構として働く。がんを防ぐ働きもあるが、様々な要因によりオートファジーの低下が起きる事が知られており、それが関連疾患に繋がる可能性が指摘されている。これまでに、ミトコンドリアの異常などがオートファジー欠損に伴う腫瘍形成の原因と考えられていたが、それが発がんに繋がる詳細なメカニズムはよく分かっていなかった。本研究では、オートファジーの異常が、がんの原因となりうるゲノム情報の変化を引き起こすメカニズムを解明した。これは新しいがん予防およびがん治療の方策を立てる際の道しるべとなるのため、続く研究により大きな社会還元が期待される。

Research Products

• [Journal Article] Autophagy Protects Integrity of Tumor Suppressors From Replication Stress (2022)
  • Author(s): Tsuyoshi Kawabata, Rei Unno, Tadashi Yamamuro, Shun Kageyama, Kanako Akamatsu, Reiko Sekiya, Toshiharu Fujita, Maiko Sakamoto, Miho Kawakatsu, Maho Hamasaki, Shinji Goto, Shuhei Nakamura, Wataru Sakai, Norisato Mitsutake, Tao-Sheng Li, Yoshinobu Ichimura, Takahiro Yasui, Masaaki Komatsu, Tamotsu Yoshimori
  • Journal Title: Sneak Peak Volume: -
  • DOI: 10.2139/ssrn.3950748
  • Open Access
• [Journal Article] Loss of RUBCN/rubicon in adipocytes mediates the upregulation of autophagy to promote the fasting response (2022)
  • Author(s): Yamamuro Tadashi、Nakamura Shuhei、Yanagawa Kyosuke、Tokumura Ayaka、Kawabata Tsuyoshi、Fukuhara Atsunori、Teranishi Hirofumi、Hamasaki Maho、Shimomura Iichiro、Yoshimori Tamotsu
  • Journal Title: Autophagy Volume: - Issue: 11 Pages: 1-11
  • DOI: 10.1080/15548627.2022.2047341
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Degradation of the Notch intracellular domain by elevated autophagy in osteoblasts promotes osteoblast differentiation and alleviates osteoporosis. (2022)
  • Author(s): Gota Yoshida, Tsuyoshi Kawabata, Hyota Takamutsu, Shotaro Saita, Shuhei Nakamura, Keizo Nishikawa, Mari Fujiwara, Yusuke Enokidani, Tadashi Yamamuro, Keisuke Tabata, Maho Hamasaki, Masaru Ishii, Atsushi Kumanogoh and Tamotsu Yoshimori
  • Journal Title: Autophagy Volume: 13 Pages: 1-10
  • Peer Reviewed
• [Journal Article] Rubicon prevents autophagic degradation of GATA4 to promote Sertoli cell function (2021)
  • Author(s): Yamamuro Tadashi et al.,
  • Journal Title: PLOS Genetics Volume: 17 Issue: 8 Pages: e1009688-e1009688
  • DOI: 10.1371/journal.pgen.1009688
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Autophagosome biogenesis and human health (2020)
  • Author(s): Kawabata Tsuyoshi、Yoshimori Tamotsu
  • Journal Title: Cell Discovery Volume: 6 Issue: 1
  • DOI: 10.1038/s41421-020-0166-y
  • Peer Reviewed / Open Access
• [Journal Article] Age-dependent loss of adipose Rubicon promotes metabolic disorders via excess autophagy (2020)
  • Author(s): Yamamuro Tadashi、Kawabata Tsuyoshi、Fukuhara Atsunori、Saita Shotaro、Nakamura Shuhei、Takeshita Hikari、Fujiwara Mari、Enokidani Yusuke、Yoshida Gota、Tabata Keisuke、Hamasaki Maho、Kuma Akiko、Yamamoto Koichi、Shimomura Iichiro、Yoshimori Tamotsu
  • Journal Title: Nature Communications Volume: 11 Issue: 1 Pages: 4150-4150
  • DOI: 10.1038/s41467-020-17985-w
  • Peer Reviewed / Open Access
• [Journal Article] Deregulated MTOR (mechanistic target of rapamycin kinase) is responsible for autophagy defects exacerbating kidney stone development (2019)
  • Author(s): Unno Rei, Kawabata Tsuyoshi, Taguchi Kazumi, Sugino Teruaki, Hamamoto Shuzo, Ando Ryosuke, Okada Atsushi, Kohri Kenjiro, Yoshimori Tamotsu, Yasui Takahiro
  • Journal Title: Autophagy Volume: E-pub Issue: 4 Pages: 709-723
  • DOI: 10.1080/15548627.2019.1635382
  • Peer Reviewed / Open Access
• [Presentation] オートファジーの異常と複製ストレスに起因するゲノム情報の破綻 (2019)
  • Author(s): 川端剛
  • Organizer: 第42回 日本分子生物学会年会
  • Invited