The ULK3 kinase is a determinant of keratinocyte self-renewal and tumorigenesis targeting the arginine methylome.

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Version: Final published version
License: CC BY 4.0
Serval ID
serval:BIB_ACC0B5090E58
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
The ULK3 kinase is a determinant of keratinocyte self-renewal and tumorigenesis targeting the arginine methylome.
Journal
Nature communications
Author(s)
Goruppi S., Clocchiatti A., Bottoni G., Di Cicco E., Ma M., Tassone B., Neel V., Demehri S., Simon C., Paolo Dotto G.
ISSN
2041-1723 (Electronic)
ISSN-L
2041-1723
Publication state
Published
Issued date
16/02/2023
Peer-reviewed
Oui
Volume
14
Number
1
Pages
887
Language
english
Notes
Publication types: Journal Article
Publication Status: epublish
Abstract
Epigenetic mechanisms oversee epidermal homeostasis and oncogenesis. The identification of kinases controlling these processes has direct therapeutic implications. We show that ULK3 is a nuclear kinase with elevated expression levels in squamous cell carcinomas (SCCs) arising in multiple body sites, including skin and Head/Neck. ULK3 loss by gene silencing or deletion reduces proliferation and clonogenicity of human keratinocytes and SCC-derived cells and affects transcription impinging on stem cell-related and metabolism programs. Mechanistically, ULK3 directly binds and regulates the activity of two histone arginine methyltransferases, PRMT1 and PRMT5 (PRMT1/5), with ULK3 loss compromising PRMT1/5 chromatin association to specific genes and overall methylation of histone H4, a shared target of these enzymes. These findings are of translational significance, as downmodulating ULK3 by RNA interference or locked antisense nucleic acids (LNAs) blunts the proliferation and tumorigenic potential of SCC cells and promotes differentiation in two orthotopic models of skin cancer.
Keywords
Humans, Epigenome, Arginine/metabolism, Keratinocytes/metabolism, Histones/metabolism, Cell Differentiation/genetics, Protein-Arginine N-Methyltransferases/metabolism, Repressor Proteins/metabolism, Protein Serine-Threonine Kinases/metabolism
Pubmed
Web of science
Open Access
Yes
Create date
28/02/2023 14:55
Last modification date
14/10/2023 6:06
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