1. The AHR target gene scinderin activates the WNT pathway by facilitating the nuclear translocation of β-catenin
- Author
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Lizbeth Perez-Castro, Niranjan Venkateswaran, Roy Garcia, Yi-Heng Hao, M. C. Lafita-Navarro, Jiwoong Kim, Dagan Segal, Etai Saponzik, Bo-Jui Chang, Reto Fiolka, Gaudenz Danuser, Lin Xu, Thomas Brabletz, and Maralice Conacci-Sorrell
- Subjects
Polychlorinated Dibenzodioxins ,Tryptophan ,Cell Biology ,Ligands ,Actins ,Receptors, Aryl Hydrocarbon ,Colonic Neoplasms ,Cytochrome P-450 CYP1A1 ,Humans ,RNA ,Environmental Pollutants ,Wnt Signaling Pathway ,beta Catenin ,Kynurenine - Abstract
The ligand-activated transcription factor aryl hydrocarbon receptor (AHR) regulates cellular detoxification, proliferation and immune evasion in a range of cell types and tissues, including cancer cells. In this study, we used RNA-sequencing to identify the signature of the AHR target genes regulated by the pollutant 2,3,7,8-tetrachlorodibenzodioxin (TCDD) and the endogenous ligand kynurenine (Kyn), a tryptophan-derived metabolite. This approach identified a signature of six genes (CYP1A1, ALDH1A3, ABCG2, ADGRF1 and SCIN) as commonly activated by endogenous or exogenous ligands of AHR in multiple colon cancer cell lines. Among these, the actin-severing protein scinderin (SCIN) was necessary for cell proliferation; SCIN downregulation limited cell proliferation and its expression increased it. SCIN expression was elevated in a subset of colon cancer patient samples, which also contained elevated β-catenin levels. Remarkably, SCIN expression promoted nuclear translocation of β-catenin and activates the WNT pathway. Our study identifies a new mechanism for adhesion-mediated signaling in which SCIN, likely via its ability to alter the actin cytoskeleton, facilitates the nuclear translocation of β-catenin. This article has an associated First Person interview with the first authors of the paper.
- Published
- 2022