Abstract
The aryl hydrocarbon receptor (AhR) plays an important role in maintaining cellular homeostasis and also in pathophysiology. For example, the interplay between the gut microbiome and microbially derived AhR ligands protects against inflammation along the gut-brain axis. The AhR and its ligands also inhibit colon carcinogenesis, but it has been reported that the AhR and its ligand kynurenine enhance glioblastoma (GBM). In this study, using both established and patient-derived GBM cells, we re-examined the role of kynurenine and the AhR in GBM, observing that kynurenine does not modulate AhR-mediated gene expression and does not affect invasion of GBM cells. Therefore, using an array of approaches, including ChIP, quantitative real-time PCR, and cell migration assays, we primarily focused on investigating the role of the AhR in GBM at the functional molecular and genomic levels. The results of transient and stable CRISPR/Cas9-mediated AhR knockdown in GBM cells indicated that loss of AhR enhances GBM tumor growth in a mouse xenograft model, increases GBM cell invasion, and up-regulates expression of pro-invasion/pro-migration genes, as determined by ingenuity pathway analysis of RNA-Seq data. We conclude that the AhR is a tumor suppressor-like gene in GBM; future studies are required to investigate whether the AhR could be a potential drug target for treating patients with GBM who express this receptor.
Highlights
The aryl hydrocarbon receptor (AhR) plays an important role in maintaining cellular homeostasis and in pathophysiology
The AhR and its ligands protect against intestinal cancer [24, 25], but this is in contrast to the reported tumor-promoting activity of the AhR and the AhR-active tryptophan metabolite kynurenine in glioblastoma (GBM) [26]
In contrast with previous studies, our data show that kynurenine exhibits minimal effects on GBM cell invasion, and results of functional, genomic, and molecular studies confirm that the AhR protects against GBM cell invasion and growth
Summary
AhR ligands and their effects are highly tissue- and response-specific because of several factors, including ligand structure– dependent induction of various receptor conformations that differentially interact with critical nuclear cofactors, and this is commonly observed with nuclear receptors that bind small molecules [13, 14]. This concept is supported by mutational analysis of the AhR, which shows that different structural classes of AhR ligands interact with different sets of amino acids in the AhR binding pocket [15,16,17,18]. In contrast with previous studies, our data show that kynurenine exhibits minimal effects on GBM cell invasion, and results of functional, genomic, and molecular studies confirm that the AhR protects against GBM cell invasion and growth
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
