RREB1 integrates RAS and TGF-β to induce fibrogenic EMT in pulmonary metastasis. MAPK-TGF-β-mediated EMT and fibrogenesis during the progression of cancer metastasis was driven by RREB1. Under TGF-β treatment, SMAD3-DHX9 and SMAD4-INO80 complexes interact with RREB1 clearing H2A.Z in chromatin, prompting genome accessibility. This alteration enhanced the transcriptional activities of EMT-TFs and fibrogenic factors, ultimately promoting pulmonary metastasis. INO80 and DHX9 molecular structures obtained from GeneCards (www.genecards.org). The figure was created with Biorender and Adobe Illustrator. CBP, CREB-binding protein; DHX9, DExH-Box helicase 9; INO80, INO80 complex ATPase subunit; KRAS, Kirsten rat sarcoma viral oncogene homolog; LUAD, lung adenocarcinoma; RRE, RAS-responsive elements; RREB1, RAS-responsive element-binding protein 1; SBE, SMAD-binding elements; SMAD, small mother against decapentaplegic; TF, transcription factors; TGF-β, transforming growth factor β.

A recent research article published by Lee et al. [1] in Cell revealed that transforming growth factor β (TGF-β) and rat sarcoma viral oncogene homolog (RAS) signaling, together trigger expression of epithelial-to-mesenchymal transition (EMT) and fibrogenic factors enhancing cancer metastasis through a precise and complex system. The authors elucidated that RAS-responsive element-binding protein 1 (RREB1)-mediated TGF-β-dependent fibrogenesis, and EMT come together to form a program to regulate cancer metastasis (Figure 1). This study enhances our understanding of the crosstalk between RAS and TGF-β in cancer metastasis, providing a potential therapeutic target.

Article Access: https://doi.org/10.1002/mog2.70016

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