Highlights
- •Patients with PSENEN mutations revealed decreased expression of PEN2 mRNA and protein.
- •Silencing PSENEN in keratinocytes affected NCT maturation and PS1 phosphorylation.
- •Knockdown of PSENEN in keratinocytes led to the activation EGFR signaling.
- •Silencing PSENEN did not obviously impact proliferation and differentiation of HaCaT.
- •PSENEN mutations alone may be insufficient to cause the development of acne inversa.
Abstract
Background
The effects of PSENEN mutations in patients with acne inversa (AI) are poorly understood. Hyperproliferation
of follicular keratinocytes and resulting occlusion may constitute the initial pathophysiology.
Objective
To investigate the effects of PSENEN knockdown on γ-secretase subunits, biological behaviors, and related signaling pathways
in keratinocytes.
Methods
HaCaT cells were divided into an experimental group (PSENEN knock down), a negative control group, and a blank control group. Whole transcriptome
sequencing was used to measure differences in mRNA expression of the whole genome;
real-time PCR and Western blotting were performed to determine the interference efficiency
and the effects of interference on the components of γ-secretase and related molecules.
CCK-8 was used to measure cell proliferation, and flow cytometry was used to measure
apoptosis and the cell cycle.
Results
A comparison of five healthy controls with three patients with PSENEN mutation (c.66delG, c.279delC, c.229_230insCACC) revealed decreased expression of
mRNA and protein in skin lesions of the experimental group. In this group, expression
of the other components of γ-secretase presenilin C-terminal fragment decreased, expression
of immature nicastrin increased, expression of mature nicastrin decreased, and expression
of anterior pharynx defective-1 remained unchanged. KEGG analysis revealed that differentially
expressed molecules were enriched in m-TOR signaling pathways. Subsequent verification
confirmed that differences in PI3K-AKT-mTOR signaling pathway molecules, cell proliferation,
apoptosis, cell cycle and the expression levels of Ki-67, KRT1, and IVL between the
groups were not statistically significant.
Conclusions
PSENEN mutations alone may be insufficient to cause the development of AI, or they may only
induce a mild phenotype of AI.
Keywords
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Article info
Publication history
Published online: June 18, 2021
Accepted:
June 16,
2021
Received in revised form:
May 11,
2021
Received:
February 16,
2021
Identification
Copyright
© 2021 Japanese Society for Investigative Dermatology. Published by Elsevier B.V. All rights reserved.
