Cannabidiol induces antioxidant pathways in keratinocytes by targeting BACH1

Laura Casares Perez, Víctor García, Martín Garrido-Rodríguez, Estrella Millán, Juan A. Collado, Adela García-Martín, Jon Peñarando, Marco A. Calzado, Laureano de la Vega (Lead / Corresponding author), Eduardo Muñoz (Lead / Corresponding author)

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Abstract

Cannabidiol (CBD) is a major non-psychotropic phytocannabinoid that attracted a great attention for its therapeutic potential against different pathologies including skin diseases. However, although the efficacy in preclinical models and the clinical benefits of CBD in humans have been extensively demonstrated, the molecular mechanism(s) and targets responsible for these effects are as yet unknown. Herein we characterized at the molecular level the effects of CBD on primary human keratinocytes using a combination of RNA sequencing (RNA-Seq) and sequential window acquisition of all theoretical mass spectrometry (SWATH-MS). Functional analysis revealed that CBD regulated pathways involved in keratinocyte differentiation, skin development and epidermal cell differentiation among other processes. In addition, CBD induced the expression of several NRF2 target genes, with heme oxygenase 1 (HMOX1) being the gene and the protein most upregulated by CBD. CRISPR/Cas9-mediated genome editing, RNA interference and biochemical studies demonstrated that the induction of HMOX1 mediated by CBD, involved nuclear export and proteasomal degradation of the transcriptional repressor BACH1. Notably, we showed that the effect of BACH1 on HMOX1 expression in keratinocytes is independent of NRF2. In vivo studies showed that topical CBD increased the levels of HMOX1 and of the proliferation and wound-repair associated keratins 16 and 17 in the skin of mice. Altogether, our study identifies BACH1 as a molecular target for CBD in keratinocytes and sets the basis for the use of topical CBD for the treatment of different skin diseases including atopic dermatitis and keratin disorders.
Original languageEnglish
Article number101321
Pages (from-to)1-15
Number of pages15
JournalRedox Biology
Volume28
Early online date5 Sep 2019
DOIs
Publication statusE-pub ahead of print - 5 Sep 2019

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Cannabidiol
Keratinocytes
Antioxidants
Heme Oxygenase-1
Skin
Skin Diseases
Keratin-16
Keratin-17
Clustered Regularly Interspaced Short Palindromic Repeats
Genes
RNA
RNA Sequence Analysis
Functional analysis
Cell Nucleus Active Transport
Pathology
Atopic Dermatitis
Keratins
RNA Interference
Mass spectrometry
Cell Differentiation

Keywords

  • Cannabidiol/ BACH1/ HMOX1/ NRF2/ Keratinocytes

Cite this

Casares Perez, L., García, V., Garrido-Rodríguez, M., Millán, E., Collado, J. A., García-Martín, A., ... Muñoz, E. (2020). Cannabidiol induces antioxidant pathways in keratinocytes by targeting BACH1. Redox Biology, 28, 1-15. [101321]. https://doi.org/10.1016/j.redox.2019.101321
Casares Perez, Laura ; García, Víctor ; Garrido-Rodríguez, Martín ; Millán, Estrella ; Collado, Juan A. ; García-Martín, Adela ; Peñarando, Jon ; Calzado, Marco A. ; de la Vega, Laureano ; Muñoz, Eduardo. / Cannabidiol induces antioxidant pathways in keratinocytes by targeting BACH1. In: Redox Biology. 2020 ; Vol. 28. pp. 1-15.
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abstract = "Cannabidiol (CBD) is a major non-psychotropic phytocannabinoid that attracted a great attention for its therapeutic potential against different pathologies including skin diseases. However, although the efficacy in preclinical models and the clinical benefits of CBD in humans have been extensively demonstrated, the molecular mechanism(s) and targets responsible for these effects are as yet unknown. Herein we characterized at the molecular level the effects of CBD on primary human keratinocytes using a combination of RNA sequencing (RNA-Seq) and sequential window acquisition of all theoretical mass spectrometry (SWATH-MS). Functional analysis revealed that CBD regulated pathways involved in keratinocyte differentiation, skin development and epidermal cell differentiation among other processes. In addition, CBD induced the expression of several NRF2 target genes, with heme oxygenase 1 (HMOX1) being the gene and the protein most upregulated by CBD. CRISPR/Cas9-mediated genome editing, RNA interference and biochemical studies demonstrated that the induction of HMOX1 mediated by CBD, involved nuclear export and proteasomal degradation of the transcriptional repressor BACH1. Notably, we showed that the effect of BACH1 on HMOX1 expression in keratinocytes is independent of NRF2. In vivo studies showed that topical CBD increased the levels of HMOX1 and of the proliferation and wound-repair associated keratins 16 and 17 in the skin of mice. Altogether, our study identifies BACH1 as a molecular target for CBD in keratinocytes and sets the basis for the use of topical CBD for the treatment of different skin diseases including atopic dermatitis and keratin disorders.",
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note = "This work was supported by the Medical Research Institute of the University of Dundee, Cancer Research UK (C52419/A22869) (LV) and Tenovus Scotland (T18/07) (LC) and by grant SAF2017-87701-R (EM) from the Ministry of the Economy and Competition (MINECO) co-financed with the European Union FEDER funds. InnoHealth Group and Emerald Health Biotechnology also supported this work and had no further role in study design, the collection, analysis and interpretation of data, in the writing of the report, or in the decision to submit the paper for publication.",
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Casares Perez, L, García, V, Garrido-Rodríguez, M, Millán, E, Collado, JA, García-Martín, A, Peñarando, J, Calzado, MA, de la Vega, L & Muñoz, E 2020, 'Cannabidiol induces antioxidant pathways in keratinocytes by targeting BACH1', Redox Biology, vol. 28, 101321, pp. 1-15. https://doi.org/10.1016/j.redox.2019.101321

Cannabidiol induces antioxidant pathways in keratinocytes by targeting BACH1. / Casares Perez, Laura; García, Víctor; Garrido-Rodríguez, Martín; Millán, Estrella; Collado, Juan A.; García-Martín, Adela; Peñarando, Jon; Calzado, Marco A.; de la Vega, Laureano (Lead / Corresponding author); Muñoz, Eduardo (Lead / Corresponding author).

In: Redox Biology, Vol. 28, 101321, 01.2020, p. 1-15.

Research output: Contribution to journalArticle

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AU - Casares Perez, Laura

AU - García, Víctor

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AU - Collado, Juan A.

AU - García-Martín, Adela

AU - Peñarando, Jon

AU - Calzado, Marco A.

AU - de la Vega, Laureano

AU - Muñoz, Eduardo

N1 - This work was supported by the Medical Research Institute of the University of Dundee, Cancer Research UK (C52419/A22869) (LV) and Tenovus Scotland (T18/07) (LC) and by grant SAF2017-87701-R (EM) from the Ministry of the Economy and Competition (MINECO) co-financed with the European Union FEDER funds. InnoHealth Group and Emerald Health Biotechnology also supported this work and had no further role in study design, the collection, analysis and interpretation of data, in the writing of the report, or in the decision to submit the paper for publication.

PY - 2019/9/5

Y1 - 2019/9/5

N2 - Cannabidiol (CBD) is a major non-psychotropic phytocannabinoid that attracted a great attention for its therapeutic potential against different pathologies including skin diseases. However, although the efficacy in preclinical models and the clinical benefits of CBD in humans have been extensively demonstrated, the molecular mechanism(s) and targets responsible for these effects are as yet unknown. Herein we characterized at the molecular level the effects of CBD on primary human keratinocytes using a combination of RNA sequencing (RNA-Seq) and sequential window acquisition of all theoretical mass spectrometry (SWATH-MS). Functional analysis revealed that CBD regulated pathways involved in keratinocyte differentiation, skin development and epidermal cell differentiation among other processes. In addition, CBD induced the expression of several NRF2 target genes, with heme oxygenase 1 (HMOX1) being the gene and the protein most upregulated by CBD. CRISPR/Cas9-mediated genome editing, RNA interference and biochemical studies demonstrated that the induction of HMOX1 mediated by CBD, involved nuclear export and proteasomal degradation of the transcriptional repressor BACH1. Notably, we showed that the effect of BACH1 on HMOX1 expression in keratinocytes is independent of NRF2. In vivo studies showed that topical CBD increased the levels of HMOX1 and of the proliferation and wound-repair associated keratins 16 and 17 in the skin of mice. Altogether, our study identifies BACH1 as a molecular target for CBD in keratinocytes and sets the basis for the use of topical CBD for the treatment of different skin diseases including atopic dermatitis and keratin disorders.

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Casares Perez L, García V, Garrido-Rodríguez M, Millán E, Collado JA, García-Martín A et al. Cannabidiol induces antioxidant pathways in keratinocytes by targeting BACH1. Redox Biology. 2020 Jan;28:1-15. 101321. https://doi.org/10.1016/j.redox.2019.101321