TY - JOUR
T1 - The AHR target gene scinderin activates the WNT pathway by facilitating the nuclear translocation of β-catenin
AU - Perez-Castro, Lizbeth
AU - Venkateswaran, Niranjan
AU - Garcia, Roy
AU - Hao, Yi Heng
AU - Lafita-Navarro, M. C.
AU - Kim, Jiwoong
AU - Segal, Dagan
AU - Saponzik, Etai
AU - Chang, Bo Jui
AU - Fiolka, Reto
AU - Danuser, Gaudenz
AU - Xu, Lin
AU - Brabletz, Thomas
AU - Conacci-Sorrell, Maralice
N1 - Publisher Copyright:
© 2022. Published by The Company of Biologists Ltd.
PY - 2022/10
Y1 - 2022/10
N2 - 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.
AB - 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.
KW - Aryl hydrocarbon receptor
KW - Colon cancer
KW - FICZ
KW - Kynurenine
KW - TCDD
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U2 - 10.1242/jcs.260028
DO - 10.1242/jcs.260028
M3 - Article
C2 - 36148682
AN - SCOPUS:85140856537
SN - 0021-9533
VL - 135
JO - Journal of cell science
JF - Journal of cell science
IS - 20
M1 - jcs260028
ER -