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ATOH8 binds SMAD3 to induce cellular senescence and prevent Ras-driven malignant transformation
- Source :
- Proceedings of the National Academy of Sciences. 120
- Publication Year :
- 2023
- Publisher :
- Proceedings of the National Academy of Sciences, 2023.
-
Abstract
- The process of oncogene-induced senescence (OIS) and the conversion between OIS and malignant transformation during carcinogenesis is poorly understood. Here, we show that following overactivation of oncogene Ras in lung epithelial cells, high-level transforming growth factor β1 (TGF-β1)–activated SMAD3, but not SMAD2 or SMAD4, plays a determinant role in inducing cellular senescence independent of the p53/p16/p15 senescence pathways. Importantly, SMAD3 binds a potential tumor suppressor ATOH8 to form a transcriptional complex that directly represses a series of cell cycle–promoting genes and consequently causes senescence in lung epithelial cells. Interestingly, the prosenescent SMAD3 converts to being oncogenic and essentially facilitates oncogenic Ras-driven malignant transformation. Furthermore, depleting Atoh8 rapidly accelerates oncogenic Ras-driven lung tumorigenesis, and lung cancers driven by mutant Ras and Atoh8 loss, but not by mutant Ras only, are sensitive to treatment of a specific SMAD3 inhibitor. Moreover, hypermethylation of the ATOH8 gene can be found in approximately 12% of clinical lung cancer cases. Together, our findings demonstrate not only epithelial cellular senescence directed by a potential tumor suppressor–controlled transcriptional program but also an important interplay between the prosenescent and transforming effects of TGF-β/SMAD3, potentially laying a foundation for developing early detection and anticancer strategies.
- Subjects :
- Multidisciplinary
Subjects
Details
- ISSN :
- 10916490 and 00278424
- Volume :
- 120
- Database :
- OpenAIRE
- Journal :
- Proceedings of the National Academy of Sciences
- Accession number :
- edsair.doi...........f909b4ca8e999475b935c13064e7e8e0