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Abstract
The aryl hydrocarbon receptor (AhR) is an environmentally responsive ligand-activated transcription factor, identified in the ‘70s for its toxic responses to halogenated polycyclic aromatic hydrocarbons, such as dioxin. Recently, AhR has been recognized as engaged in multiple physiological processes in health and diseases, particularly in the immune system, inflammatory response, tumorigenesis, and cellular differentiation by epigenetic mechanisms involving miRNAs. However, there is still scarce information about AhR-dependent miRNA regulation and miRNA-mediated epigenetic control in pathologies and therapies. In this review, we explore the mutual regulation of AhR and miRNA over the last decade of studies since many miRNAs have dioxin response elements (DRE) in their 3’ UTR, as well as AhR might contain binding sites of miRNAs. TCDD is the most used ligand to investigate the impact of AhR activation, and the immune system is one of the most sensitive of its targets. An association between TCDD-activated AhR and epigenetic mechanisms like post-transcriptional regulation by miRNAs, DNA methylation, or histone modification has already been confirmed. Besides, several studies have shown that AhR-induced miR-212/132 cluster suppresses cancers, attenuates autoimmune diseases, and has an anti-inflammatory role in different immune responses by regulating cytokine levels and immune cells. Together the ever-expanding new AhR roles and the miRNA therapeutics are a prominent segment among biopharmaceuticals. Additionally, AhR-activated miRNAs can serve as valuable biomarkers of diseases, notably cancer progression or suppression and chemical exposure. Once AhR-dependent gene expression may hinge on the ligand, cell type, and context singularity, the reviewed outcomes might help contextualize state of the art and support new trends and emerging opportunities in the field.
Highlights
The aryl hydrocarbon receptor (AhR) is a cytosolic liganddependent transcription factor and environmental sensor which belongs to the basic helix-loop-helix— periodic circadian protein (PER)—AhR nuclear translocator (ARNT)—single-minded protein (SIM) superfamily of transcription factors, which PER-ARNT-SIM (PAS) domain acts as a sensor of endogenous and exogenous factors (Nguyen and Bradfield, 2008)
We focused on novel pathways where AhR is involved beyond the environmental toxicity response, such as inflammatory response, metabolism, carcinogenesis, cellular differentiation and proliferation, and additional biological processes post-transcriptionally controlled by miRNAs after AhR modulation
The inhibitory effects of TCDD on the proliferation and invasion of prostate cancer cells were demonstrated by Yu et al (2018); AhR enhanced the expression of miR-150-5p, which regulates MAP3K12. miR150-5p might act as a suppressor of carcinogenesis once there is evidence of its low expression in prostate cancer tissues compared to non-tumorous control
Summary
The aryl hydrocarbon receptor (AhR) is a cytosolic liganddependent transcription factor and environmental sensor which belongs to the basic helix-loop-helix (bHLH)— periodic circadian protein (PER)—AhR nuclear translocator (ARNT)—single-minded protein (SIM) superfamily of transcription factors, which PER-ARNT-SIM (PAS) domain acts as a sensor of endogenous and exogenous factors (Nguyen and Bradfield, 2008). Zhang et al (2012) reported that TCDD inhibited breast cancer cell invasion by inducing miR-335 and decreased SOX4 (a miR-335-regulated gene) expression.
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