Insight into the relationship between aryl-hydrocarbon receptor and β-catenin in human colon cancer cells

Abstract

β-Catenin is a multi-functional protein involved in cell adhesion and signal transduction and has a critical role in colorectal cancer development. β-Catenin positively regulates the aryl-hydrocarbon receptor (AhR) mediated signal by both induction of AhR expression and enhancement of AhR-dependent gene induction. Conversely, it was reported that AhR negatively regulates the β-catenin signal via ubiquitination and subsequent degradation in a ligand dependent manner. However, there have been conflicting data among previous studies regarding the relationship between these two proteins. In this report, we conducted confirmatory studies dissecting the relationship between AhR and β-catenin. We did not observe β-catenin degradation by AhR ligands in several colon cancer cell lines. Reporter assays revealed that the AhR ligand did not alter TcF/β-catenin dependent transcription. Yeast and mammalian two-hybrid assays failed to reconstruct the interaction of β-catenin and AhR even when other factors, Arnt, CUL4B, and DDB1, were co-expressed additionally. Independently to induction of AhR expression, β-catenin enhanced AhR-dependent transcriptional activation via the xenobiotic response element (XRE). Coimmunoprecipitation detected the formation of a β-catenin and ligand-activated AhR complex, which was thought to reflect the β-catenin mediated enhancement of the AhR signaling. Overall, we could only confirm unidirectional interaction, which is positive regulation of the AhR signal by β-catenin. These results suggested that data from previous reports on the degradation of β-catenin via liganded AhR warrants further investigation to yield clarity in the field.

AhR and Cancer: from Gene Profiling to Targeted Therapy

“…Shiizaki et al showed that AhR activation induces β-catenin ubiquitination and subsequent proteosomal degradation. Thus AhR −/− mice spontaneously developed cecal tumors as the result of aberrant β-catenin accumulation [52] [53]. Similarly, treatment with TCDD (0.1-100 nM) diminishes colony formation and proliferation of human colorectal cancer cells [54].…”

AhR and Cancer: From Gene Profiling to Targeted Therapy

“…Shiizaki et al showed that AhR activation induces β-catenin ubiquitination and subsequent proteosomal degradation. Thus, AhR −/− mice spontaneously developed cecal tumors as the result of aberrant β-catenin accumulation [ 52 , 53 ]. Similarly, treatment with TCDD (0.1–100 nM) diminishes colony formation and proliferation of human colorectal cancer cells [ 54 ].…”

Overexpression of G3BP1 facilitates the progression of colon cancer by activating β‑catenin signaling

“…While it has been reported that the Wnt/β-catenin signaling pathway serves an important role in the progression of colon cancer (19,20), the mechanism underlying its hyperactivation is not fully understood. in the current study, it was demonstrated that the increased expression levels of β-catenin and c-myc proteins, together with the nuclear accumulation of β-catenin protein, could be induced by G3BP1 overexpression, with no notable change in the expression levels of Frz, Dsh, TCF, Axin and APC.…”

“…However, the mechanisms via which G3BP1 facilitates colon cancer progression and the clinical values of G3BP1 require further investigation. Previous studies have revealed that aberration of the Wnt/β-catenin signaling pathway significantly contributes to the malignant transformation of colon cancer (19,20). inhibition of Wnt/β-catenin is suggested to be an anti-tumor mechanism in colon cancer (21).…”

“…Previous studies have revealed that aberration of the Wnt/β-catenin signaling pathway significantly contributes to the malignant transformation of colon cancer ( 19 , 20 ). Inhibition of Wnt/β-catenin is suggested to be an anti-tumor mechanism in colon cancer ( 21 ).…”