Research Papers:

Xenobiotic-induced activation of human aryl hydrocarbon receptor target genes in Drosophila is mediated by the epigenetic chromatin modifiers

Angelina A. Akishina, Julia E. Vorontsova, Roman O. Cherezov, Il’ya B. Mertsalov, Olga G. Zatsepina, Mikhail S. Slezinger, Vladislav M. Panin, Svetlana Petruk, Grigori N. Enikolopov, Alexander Mazo, Olga B. Simonova _ and Boris A. Kuzin

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Oncotarget. 2017; 8:102934-102947. https://doi.org/10.18632/oncotarget.22173

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Angelina A. Akishina1,*, Julia E. Vorontsova1,*, Roman O. Cherezov1, Il’ya B. Mertsalov1, Olga G. Zatsepina2, Mikhail S. Slezinger1, Vladislav M. Panin3, Svetlana Petruk4, Grigori N. Enikolopov5, Alexander Mazo4, Olga B. Simonova1 and Boris A. Kuzin1

1Kol’tsov Institute of Developmental Biology, Russian Academy of Sciences, Moscow, Russia

2Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Moscow, Russia

3Department of Biochemistry and Biophysics, Texas A&M University, College Station, TX, USA

4Department of Biochemistry and Molecular Biology and Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA, USA

5Center for Developmental Genetics, Department of Anesthesiology, Stony Brook University, Stony Brook, NY, USA

*These authors contributed equally to this work

Correspondence to:

Olga B. Simonova, email: [email protected]

Keywords: xenobiotic; aryl hydrocarbon receptor; PcG epigenetic complexes; drosophila

Received: May 19, 2017     Accepted: October 13, 2017     Published: October 31, 2017


Aryl hydrocarbon receptor (AHR) is the key transcription factor that controls animal development and various adaptive processes. The AHR’s target genes are involved in biodegradation of endogenous and exogenous toxins, regulation of immune response, organogenesis, and neurogenesis. Ligand binding is important for the activation of the AHR signaling pathway. Invertebrate AHR homologs are activated by endogenous ligands whereas vertebrate AHR can be activated by both endogenous and exogenous ligands (xenobiotics). Several studies using mammalian cultured cells have demonstrated that transcription of the AHR target genes can be activated by exogenous AHR ligands, but little is known about the effects of AHR in a living organism. Here, we examined the effects of human AHR and its ligands using transgenic Drosophila lines with an inducible human AhR gene. We found that exogenous AHR ligands can increase as well as decrease the transcription levels of the AHR target genes, including genes that control proliferation, motility, polarization, and programmed cell death. This suggests that AHR activation may affect the expression of gene networks that could be critical for cancer progression and metastasis. Importantly, we found that AHR target genes are also controlled by the enzymes that modify chromatin structure, in particular components of the epigenetic Polycomb Repressive complexes 1 and 2. Since exogenous AHR ligands (alternatively – xenobiotics) and small molecule inhibitors of epigenetic modifiers are often used as pharmaceutical anticancer drugs, our findings may have significant implications in designing new combinations of therapeutic treatments for oncological diseases.

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