2025-03-13 北海道大学
<関連情報>
- https://www.hokudai.ac.jp/news/2025/03/post-1820.html
- https://www.hokudai.ac.jp/news/pdf/250313_pr.pdf
- https://www.cell.com/iscience/fulltext/S2589-0042(25)00317-7
硬い足場は転写因子ATF5を活性化することでがん細胞の増殖を誘導する Stiff extracellular matrix activates the transcription factor ATF5 to promote the proliferation of cancer cells
Seiichiro Ishihara∙ Atsushi Enomoto∙ Akihiro Sakai∙ … ∙ Motoaki Yasuda∙ Takashi Tokino∙ Hisashi Haga
iScience Published:February 17, 2025
DOI:https://doi.org/10.1016/j.isci.2025.112057
Graphical abstract
Highlights
- Stiff ECMs trigger ATF5 nuclear localization in cancer cell lines and tumor tissues
- Stiff ECMs promote the proliferation of cancer cells via ATF5 activation
- ATF5 activation by stiff ECMs suppresses EGR1 expression in cancer cells
- Stiff ECMs induce the integrin-JAK-MYC and actomyosin-MYC pathways to activate ATF5
Summary
Cancer tissues are stiffer than normal tissues. Carcinogenesis stiffens the extracellular matrix (ECM) of cancerous tissues, to which cancer cells respond by activating transcription factors, such as YAP/TAZ, Twist1, and β-catenin, which further elevate their malignancy. However, these transcription factors are also expressed in normal tissues. Therefore, inhibiting these factors in order to treat cancer may lead to severe side effects. Here, we show that activating transcription factor 5 (ATF5), highly expressed in tumors, is activated by ECM stiffness and promotes the proliferation of cancer cells, including that of pancreatic cancer cells and lung cancer cells. In addition, ATF5 suppressed the expression of early growth response 1 (EGR1), thereby accelerating cancer cell proliferation. Stiff ECMs trigger the JAK-MYC pathway which activates ATF5. JAK activation was actomyosin independent whereas MYC induction was actomyosin dependent. These results demonstrate the critical role played by ATF5 in the mechanotransduction process seen in cancers.
