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The Polyamine Regulator AMD1 Upregulates Spermine Levels to Drive Epidermal Differentiation

Lookup NU author(s): Professor John Common

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Abstract

© 2021 The Authors. Maintaining tissue homeostasis depends on a balance between cell proliferation, differentiation, and apoptosis. Within the epidermis, the levels of the polyamines putrescine, spermidine, and spermine are altered in many different skin conditions, yet their role in epidermal tissue homeostasis is poorly understood. We identify the polyamine regulator, Adenosylmethionine decarboxylase 1 (AMD1), as a crucial regulator of keratinocyte (KC) differentiation. AMD1 protein is upregulated on differentiation and is highly expressed in the suprabasal layers of the human epidermis. During KC differentiation, elevated AMD1 promotes decreased putrescine and increased spermine levels. Knockdown or inhibition of AMD1 results in reduced spermine levels and inhibition of KC differentiation. Supplementing AMD1-knockdown KCs with exogenous spermidine or spermine rescued aberrant differentiation. We show that the polyamine shift is critical for the regulation of key transcription factors and signaling proteins that drive KC differentiation, including KLF4 and ZNF750. These findings show that human KCs use controlled changes in polyamine levels to modulate gene expression to drive cellular behavior changes. Modulation of polyamine levels during epidermal differentiation could impact skin barrier formation or can be used in the treatment of hyperproliferative skin disorders.

Publication metadata

Author(s): Rahim AB, Lim HK, Tan CYR, Jia L, Leo VI, Uemura T, Hardman-Smart J, Common JEA, Lim TC, Bellanger S, Paus R, Igarashi K, Yang H, Vardy LA

Publication type: Article

Publication status: Published

Journal: Journal of Investigative Dermatology

Year: 2021

Volume: 141

Issue: 9

Pages: 2178-2188.e6

Print publication date: 01/09/2021

Online publication date: 11/05/2021

Acceptance date: 27/01/2021

ISSN (print): 0022-202X

ISSN (electronic): 1523-1747

Publisher: Elsevier BV

URL: https://doi.org/10.1016/j.jid.2021.01.039

DOI: 10.1016/j.jid.2021.01.039

PubMed id: 33984347

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