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-seq to identify the signature of 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, ADGFR1, 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 is elevated in a subset of colon cancer patient samples, which also contain elevated β-catenin levels. Remarkably, SCIN expression promotes nuclear translocation of β-catenin and activates the WNT pathway. Our study identified 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.
The AHR target gene Scinderin activates the WNT pathway by facilitating the nuclear translocation of β-catenin
These authors contributed equally to the work
- Award Group:
- Funder(s): Cancer Prevention and Research Institute of Texas
- Award Id(s): RP220046
- Funder(s):
- Award Group:
- Funder(s): American Cancer Society
- Award Id(s): 724003
- Funder(s):
- Award Group:
- Funder(s): Welch Foundation
- Award Id(s): I-2058-20210327
- Funder(s):
- Award Group:
- Funder(s): Division of Cancer Prevention, National Cancer Institute
- Award Id(s): R01CA245548
- Funder(s):
- Award Group:
- Funder(s): General Medicine
- Award Id(s): R01 GM145744-01
- Funder(s):
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Lizbeth Perez-Castro, Niranjan Venkateswaran, Roy Garcia, Yi-Heng Hao, M. Carmen Lafita-Navarro, Jiwoong Kim, Dagan Segal, Etai Saponzik, Bo-Jui Chang, Reto Fiolka, Gaudenz Danuser, Lin Xu, Thomas Brabletz, Maralice Conacci-Sorrell; The AHR target gene Scinderin activates the WNT pathway by facilitating the nuclear translocation of β-catenin. J Cell Sci 2022; jcs.260028. doi: https://doi.org/10.1242/jcs.260028
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