ATOH8 binds SMAD3 to induce cellular senescence and prevent Ras-driven malignant transformation

Proc Natl Acad Sci U S A. 2023 Jan 17;120(3):e2208927120. doi: 10.1073/pnas.2208927120. Epub 2023 Jan 10.

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.

Keywords: Ras; SMAD3; TGF-β; cellular senescence; malignant transformation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Basic Helix-Loop-Helix Transcription Factors* / genetics
  • Basic Helix-Loop-Helix Transcription Factors* / metabolism
  • Cell Transformation, Neoplastic* / genetics
  • Cellular Senescence / genetics
  • Genes, Tumor Suppressor
  • Genes, ras*
  • Humans
  • Smad3 Protein* / genetics
  • Smad3 Protein* / metabolism
  • Transforming Growth Factor beta / metabolism

Substances

  • Smad3 Protein
  • SMAD3 protein, human
  • Transforming Growth Factor beta
  • ATOH8 protein, human
  • Basic Helix-Loop-Helix Transcription Factors