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Updated: Jun 19, 2026
Characterization of In Vitro Differentiation of Human Primary Keratinocytes by RNA-Seq Analysis
Published on: May 16, 2020
Gene regulation of CYP4F11 in human keratinocyte HaCaT cells
Ying Wang1, Jordan C Bell, Diane S Keeney
1Department of Biochemistry and Molecular Biology, the University of Texas-Houston Medical School, Houston, Texas, USA.
Abstract:
Mechanisms regulating CYP4F genes remain under investigation, although characterization of CYP4F regulatory modalities would facilitate the discovery of new drug targets. This present study shows that all-trans- and 9-cis-retinoic acids can inhibit CYP4F11 expression in human keratinocyte-derived HaCaT cells. Transrepression of many genes by retinoic acids is mediated by interactions between retinoid receptors and the activator protein 1 (AP-1) complex. Proinflammatory cytokines tumor necrosis factor alpha (TNF-alpha) and interleukin 1beta, which can activate the AP-1 complex, induce CYP4F11 transcription in HaCaT cells. The c-Jun N-terminal kinase (JNK)-specific inhibitor 1,9-pyrazoloanthrone (SP600125) blocked the induction of CYP4F11 by both cytokines, indicating involvement of the JNK pathway. Furthermore, TNF-alpha failed to induce CYP4F11 transcription when HaCaT cells were preincubated with retinoic acids. Retinoic acids are ligands for the retinoic acid receptors (RARs) and the retinoid X receptors (RXRs). The RXR agonist 6-(1(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydronaphthalen-2-yl)cyclopropyl) nicotinic acid (LG268) greatly induced CYP4F11 transcription, whereas the RAR agonist 4-(2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)-1-propenyl)benzoic acid (TTNPB) markedly inhibited CYP4F11 transcription, indicating that down-regulation of CYP4F11 transcription by retinoic acid is mediated by RARs and may also be related to ligand competition for RXRs. Thus, the CYP4F11 gene is positively regulated by multiple signaling pathways in HaCaT keratinocytes, including RXR and JNK signaling pathways.
Insights
Retinoic acids regulate CYP4F11 gene expression in skin cells. Retinoic acid receptors (RARs) inhibit, while retinoid X receptors (RXRs) and JNK pathways activate, CYP4F11, influencing drug target discovery.
Area of Science:
- Biochemistry
- Molecular Biology
- Dermatology
Background:
- CYP4F gene regulation is not fully understood, hindering drug target identification.
- Retinoic acids are known regulators of gene expression, often via retinoid receptors and AP-1 complex interactions.
Purpose of the Study:
- To investigate the regulatory mechanisms of CYP4F11 gene expression in human keratinocytes.
- To elucidate the role of retinoic acids, inflammatory cytokines, and specific signaling pathways in CYP4F11 regulation.
Main Methods:
- Utilized human keratinocyte-derived HaCaT cells.
- Administered all-trans-retinoic acid, 9-cis-retinoic acid, RXR agonist (LG268), and RAR agonist (TTNPB).
- Assessed CYP4F11 expression following treatment with tumor necrosis factor alpha (TNF-alpha), interleukin 1beta, and JNK inhibitor (SP600125).
Main Results:
- Retinoic acids inhibited CYP4F11 expression in HaCaT cells.
- Proinflammatory cytokines TNF-alpha and IL-1beta induced CYP4F11 transcription via the JNK pathway.
- RAR activation inhibited, while RXR activation induced, CYP4F11 transcription, suggesting dual regulation by retinoic acid receptors.
Conclusions:
- CYP4F11 gene expression is positively regulated by RXR and JNK signaling pathways in keratinocytes.
- Down-regulation by retinoic acid is mediated by RARs and potentially influenced by RXR ligand competition.
- Understanding these regulatory pathways offers potential for novel drug target discovery.
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