Xenobiotic CAR activators induce Dlk1-Dio3 locus non-coding RNA expression in mouse liver

Lucie Pouché; Antonio Vitobello; Michael  Römer; Milica  Glogovac; A. Kenneth MacLeod; Heidrun Ellinger-Ziegelbauer; Magdalena  Westphal; Valérie  Dubost; Daniel Philipp  Stiehl; Bérengère  Dumotier; Alexander Fekete; Pierre Moulin; Andreas Zell; Michael Schwarz; Rita Moreno; Jeffrey T. J. Huang; Cliff R. Elcombe; Colin J. Henderson; C. Roland Wolf; Jonathan G. Moggs; Rémi  Terranova

doi:10.1093/toxsci/kfx104

Xenobiotic CAR activators induce Dlk1-Dio3 locus non-coding RNA expression in mouse liver

Lucie Pouché , Antonio Vitobello, Michael Römer, Milica Glogovac, A. Kenneth MacLeod, Heidrun Ellinger-Ziegelbauer, Magdalena Westphal, Valérie Dubost, Daniel Philipp Stiehl, Bérengère Dumotier, Alexander Fekete, Pierre Moulin, Andreas Zell, Michael Schwarz, Rita Moreno , Jeffrey T. J. Huang, Cliff R. Elcombe, Colin J. Henderson, C. Roland Wolf, Jonathan G. MoggsRémi Terranova (Lead / Corresponding author)

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Abstract

Derisking xenobiotic-induced non-genotoxic carcinogenesis (NGC) represents a significant challenge during the safety assessment of chemicals and therapeutic drugs. The identification of robust mechanism-based NGC biomarkers has the potential to enhance cancer hazard identification. We previously demonstrated Constitutive Androstane Receptor (CAR) and WNT signaling-dependent up-regulation of the pluripotency associated Dlk1-Dio3 imprinted gene cluster non-coding RNAs (ncRNAs) in the liver of mice treated with tumor-promoting doses of phenobarbital (PB). Here, we have compared phenotypic, transcriptional and proteomic data from wild-type, CAR/PXR double knock-out and CAR/PXR double humanized mice treated with either PB or chlordane, and show that hepatic Dlk1-Dio3 locus long ncRNAs are upregulated in a CAR/PXR-dependent manner by two structurally distinct CAR activators. We further explored the specificity of Dlk1-Dio3 locus ncRNAs as hepatic NGC biomarkers in mice treated with additional compounds working through distinct NGC modes of action. We propose that up-regulation of Dlk1-Dio3 cluster ncRNAs can serve as an early biomarker for CAR activator-induced non-genotoxic hepatocarcinogenesis and thus may contribute to mechanism-based assessments of carcinogenicity risk for chemicals and novel therapeutics.

Original language	English
Pages (from-to)	367-378
Number of pages	11
Journal	Toxicological Sciences
Volume	158
Issue number	2
Early online date	25 May 2017
DOIs	https://doi.org/10.1093/toxsci/kfx104
Publication status	Published - Aug 2017

Keywords

Dlk1-Dio3 cluster
Non-coding RNAs
Constitutive Androstane Receptor (CAR)
Non-genotoxic Carcinogenesis (NGC)
Cancer risk assessment
Phenobarbital
Chlordane

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1093/toxsci/kfx104

Author Accepted ManuscriptAccepted author manuscript, 5.23 MB

Wolf, Roland
- Cancer Research - Professor (Teaching and Research) of Molecular Pharmacology
Person: Academic

Cite this

Pouché , L., Vitobello, A., Römer, M., Glogovac, M., MacLeod, A. K., Ellinger-Ziegelbauer, H., Westphal, M., Dubost, V., Stiehl, D. P., Dumotier, B., Fekete, A., Moulin, P., Zell, A., Schwarz, M., Moreno , R., Huang, J. T. J., Elcombe, C. R., Henderson, C. J., Wolf, C. R., ... Terranova, R. (2017). Xenobiotic CAR activators induce Dlk1-Dio3 locus non-coding RNA expression in mouse liver. Toxicological Sciences, 158(2), 367-378. https://doi.org/10.1093/toxsci/kfx104

@article{343795209e87413199fc9ded1bf6e023,

title = "Xenobiotic CAR activators induce Dlk1-Dio3 locus non-coding RNA expression in mouse liver",

abstract = "Derisking xenobiotic-induced non-genotoxic carcinogenesis (NGC) represents a significant challenge during the safety assessment of chemicals and therapeutic drugs. The identification of robust mechanism-based NGC biomarkers has the potential to enhance cancer hazard identification. We previously demonstrated Constitutive Androstane Receptor (CAR) and WNT signaling-dependent up-regulation of the pluripotency associated Dlk1-Dio3 imprinted gene cluster non-coding RNAs (ncRNAs) in the liver of mice treated with tumor-promoting doses of phenobarbital (PB). Here, we have compared phenotypic, transcriptional and proteomic data from wild-type, CAR/PXR double knock-out and CAR/PXR double humanized mice treated with either PB or chlordane, and show that hepatic Dlk1-Dio3 locus long ncRNAs are upregulated in a CAR/PXR-dependent manner by two structurally distinct CAR activators. We further explored the specificity of Dlk1-Dio3 locus ncRNAs as hepatic NGC biomarkers in mice treated with additional compounds working through distinct NGC modes of action. We propose that up-regulation of Dlk1-Dio3 cluster ncRNAs can serve as an early biomarker for CAR activator-induced non-genotoxic hepatocarcinogenesis and thus may contribute to mechanism-based assessments of carcinogenicity risk for chemicals and novel therapeutics.",

keywords = "Dlk1-Dio3 cluster , Non-coding RNAs , Constitutive Androstane Receptor (CAR) , Non-genotoxic Carcinogenesis (NGC) , Cancer risk assessment , Phenobarbital, Chlordane",

author = "Lucie Pouch{\'e} and Antonio Vitobello and Michael R{\"o}mer and Milica Glogovac and MacLeod, {A. Kenneth} and Heidrun Ellinger-Ziegelbauer and Magdalena Westphal and Val{\'e}rie Dubost and Stiehl, {Daniel Philipp} and B{\'e}reng{\`e}re Dumotier and Alexander Fekete and Pierre Moulin and Andreas Zell and Michael Schwarz and Rita Moreno and Huang, {Jeffrey T. J.} and Elcombe, {Cliff R.} and Henderson, {Colin J.} and Wolf, {C. Roland} and Moggs, {Jonathan G.} and R{\'e}mi Terranova",

note = "Innovative Medicine Initiative Joint Undertaking (IMI JU) (115001) (MARCAR project; http://www.imi-marcar.eu/). This work was also supported by Cancer Research UK program grant C4639/A10822 awarded to C.R.W. All IMI-MARCAR consortium partners had a role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. We would like to thank Sarah Brasa, Harri Lempi{\"a}inen for experimental and in vivo study support and Serge Winter and Wei Wu for the pharmacokinetics analyses of chlordane and Phenobarbital studies. We would like also to thank Chi-Hse Teng for the statistical analysis support. M.G., M.W., V.D., D.P.S., B.D., P.M., J.G.M. and R.T. are full time employees of Novartis Pharma. A.V. is a recipient of a Novartis Institutes for Biomedical Research Postdoctoral Fellowships. H.E.Z. is a full time employee of Bayer. C.R.E. is a full time employee of CXR Biosciences.",

year = "2017",

month = aug,

doi = "10.1093/toxsci/kfx104",

language = "English",

volume = "158",

pages = "367--378",

journal = "Toxicological Sciences",

issn = "1096-6080",

publisher = "Oxford University Press",

number = "2",

}

Pouché , L, Vitobello, A, Römer, M, Glogovac, M, MacLeod, AK, Ellinger-Ziegelbauer, H, Westphal, M, Dubost, V, Stiehl, DP, Dumotier, B, Fekete, A, Moulin, P, Zell, A, Schwarz, M, Moreno , R, Huang, JTJ, Elcombe, CR, Henderson, CJ , Wolf, CR, Moggs, JG & Terranova, R 2017, 'Xenobiotic CAR activators induce Dlk1-Dio3 locus non-coding RNA expression in mouse liver', Toxicological Sciences, vol. 158, no. 2, pp. 367-378. https://doi.org/10.1093/toxsci/kfx104

TY - JOUR

T1 - Xenobiotic CAR activators induce Dlk1-Dio3 locus non-coding RNA expression in mouse liver

AU - Pouché , Lucie

AU - Vitobello, Antonio

AU - Römer, Michael

AU - Glogovac, Milica

AU - MacLeod, A. Kenneth

AU - Ellinger-Ziegelbauer, Heidrun

AU - Westphal, Magdalena

AU - Dubost, Valérie

AU - Stiehl, Daniel Philipp

AU - Dumotier, Bérengère

AU - Fekete, Alexander

AU - Moulin, Pierre

AU - Zell, Andreas

AU - Schwarz, Michael

AU - Moreno , Rita

AU - Huang, Jeffrey T. J.

AU - Elcombe, Cliff R.

AU - Henderson, Colin J.

AU - Wolf, C. Roland

AU - Moggs, Jonathan G.

AU - Terranova, Rémi

N1 - Innovative Medicine Initiative Joint Undertaking (IMI JU) (115001) (MARCAR project; http://www.imi-marcar.eu/). This work was also supported by Cancer Research UK program grant C4639/A10822 awarded to C.R.W. All IMI-MARCAR consortium partners had a role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. We would like to thank Sarah Brasa, Harri Lempiäinen for experimental and in vivo study support and Serge Winter and Wei Wu for the pharmacokinetics analyses of chlordane and Phenobarbital studies. We would like also to thank Chi-Hse Teng for the statistical analysis support. M.G., M.W., V.D., D.P.S., B.D., P.M., J.G.M. and R.T. are full time employees of Novartis Pharma. A.V. is a recipient of a Novartis Institutes for Biomedical Research Postdoctoral Fellowships. H.E.Z. is a full time employee of Bayer. C.R.E. is a full time employee of CXR Biosciences.

PY - 2017/8

Y1 - 2017/8

N2 - Derisking xenobiotic-induced non-genotoxic carcinogenesis (NGC) represents a significant challenge during the safety assessment of chemicals and therapeutic drugs. The identification of robust mechanism-based NGC biomarkers has the potential to enhance cancer hazard identification. We previously demonstrated Constitutive Androstane Receptor (CAR) and WNT signaling-dependent up-regulation of the pluripotency associated Dlk1-Dio3 imprinted gene cluster non-coding RNAs (ncRNAs) in the liver of mice treated with tumor-promoting doses of phenobarbital (PB). Here, we have compared phenotypic, transcriptional and proteomic data from wild-type, CAR/PXR double knock-out and CAR/PXR double humanized mice treated with either PB or chlordane, and show that hepatic Dlk1-Dio3 locus long ncRNAs are upregulated in a CAR/PXR-dependent manner by two structurally distinct CAR activators. We further explored the specificity of Dlk1-Dio3 locus ncRNAs as hepatic NGC biomarkers in mice treated with additional compounds working through distinct NGC modes of action. We propose that up-regulation of Dlk1-Dio3 cluster ncRNAs can serve as an early biomarker for CAR activator-induced non-genotoxic hepatocarcinogenesis and thus may contribute to mechanism-based assessments of carcinogenicity risk for chemicals and novel therapeutics.

AB - Derisking xenobiotic-induced non-genotoxic carcinogenesis (NGC) represents a significant challenge during the safety assessment of chemicals and therapeutic drugs. The identification of robust mechanism-based NGC biomarkers has the potential to enhance cancer hazard identification. We previously demonstrated Constitutive Androstane Receptor (CAR) and WNT signaling-dependent up-regulation of the pluripotency associated Dlk1-Dio3 imprinted gene cluster non-coding RNAs (ncRNAs) in the liver of mice treated with tumor-promoting doses of phenobarbital (PB). Here, we have compared phenotypic, transcriptional and proteomic data from wild-type, CAR/PXR double knock-out and CAR/PXR double humanized mice treated with either PB or chlordane, and show that hepatic Dlk1-Dio3 locus long ncRNAs are upregulated in a CAR/PXR-dependent manner by two structurally distinct CAR activators. We further explored the specificity of Dlk1-Dio3 locus ncRNAs as hepatic NGC biomarkers in mice treated with additional compounds working through distinct NGC modes of action. We propose that up-regulation of Dlk1-Dio3 cluster ncRNAs can serve as an early biomarker for CAR activator-induced non-genotoxic hepatocarcinogenesis and thus may contribute to mechanism-based assessments of carcinogenicity risk for chemicals and novel therapeutics.

KW - Dlk1-Dio3 cluster

KW - Non-coding RNAs

KW - Constitutive Androstane Receptor (CAR)

KW - Non-genotoxic Carcinogenesis (NGC)

KW - Cancer risk assessment

KW - Phenobarbital

KW - Chlordane

U2 - 10.1093/toxsci/kfx104

DO - 10.1093/toxsci/kfx104

M3 - Article

C2 - 28541575

SN - 1096-6080

VL - 158

SP - 367

EP - 378

JO - Toxicological Sciences

JF - Toxicological Sciences

IS - 2

ER -

Xenobiotic CAR activators induce Dlk1-Dio3 locus non-coding RNA expression in mouse liver

Abstract

Keywords

UN SDGs

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Wolf, Roland

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