The aryl hydrocarbon receptor is a tumor suppressor-like gene in glioblastoma.

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.

• Authors: Un-Ho Jin, Keshav Karki, Yating Cheng, Sharon K Michelhaugh, Sandeep Mittal, Stephen Safe
• Journal: The Journal of biological chemistry (J Biol Chem) Vol. 294 Issue 29 Pg. 11342-11353 (07 19 2019) ISSN: 1083-351X [Electronic] United States
• PMID: 31171720 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: © 2019 Jin et al.

Chemical References

• AHR protein, human
• Basic Helix-Loop-Helix Transcription Factors
• Receptors, Aryl Hydrocarbon
• Kynurenine

Topics

• Animals
• Basic Helix-Loop-Helix Transcription Factors (genetics, metabolism)
• Brain Neoplasms (genetics, pathology)
• CRISPR-Cas Systems
• Cell Line, Tumor
• Cell Proliferation
• Female
• Gene Knockdown Techniques
• Genes, Tumor Suppressor
• Glioblastoma (genetics, pathology)
• Heterografts
• Humans
• Kynurenine (metabolism)
• Mice
• Mice, Nude
• Protein Binding
• Receptors, Aryl Hydrocarbon (genetics, metabolism)