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

Sandro Goruppi; Andrea Clocchiatti; Giulia Bottoni; Emery Di Cicco; Min Ma; Beatrice Tassone; Victor Neel; Shadhmer Demehri; Christian Simon; G Paolo Dotto

doi:10.1038/s41467-023-36410-6

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

Nat Commun. 2023 Feb 16;14(1):887. doi: 10.1038/s41467-023-36410-6.

Authors

Sandro Goruppi^{1

2}, Andrea Clocchiatti^{3

4}, Giulia Bottoni^{3

4}, Emery Di Cicco^{3

4}, Min Ma^{5

6}, Beatrice Tassone^{5

6}, Victor Neel⁴, Shadhmer Demehri^{3

4}, Christian Simon^{5

6

7}, G Paolo Dotto^{8

9

10

11

12}

Affiliations

¹ Cutaneous Biology Research Center, Massachusetts General Hospital, Charlestown, 02129, MA, USA. [email protected].
² Department of Dermatology, Massachusetts General Hospital and Harvard Medical School, Boston, 02114, MA, USA. [email protected].
³ Cutaneous Biology Research Center, Massachusetts General Hospital, Charlestown, 02129, MA, USA.
⁴ Department of Dermatology, Massachusetts General Hospital and Harvard Medical School, Boston, 02114, MA, USA.
⁵ Personalized Cancer Prevention Research Unit and Head and Neck Surgery Division, Centre Hospitalier Universitaire Vaudois, Lausanne, 1011, Switzerland.
⁶ Department of Immunobiology, University of Lausanne, Epalinges, 1066, Switzerland.
⁷ International Cancer Prevention Institute, Epalinges, 1066, Switzerland.
⁸ Cutaneous Biology Research Center, Massachusetts General Hospital, Charlestown, 02129, MA, USA. [email protected].
⁹ Department of Dermatology, Massachusetts General Hospital and Harvard Medical School, Boston, 02114, MA, USA. [email protected].
¹⁰ Personalized Cancer Prevention Research Unit and Head and Neck Surgery Division, Centre Hospitalier Universitaire Vaudois, Lausanne, 1011, Switzerland. [email protected].
¹¹ Department of Immunobiology, University of Lausanne, Epalinges, 1066, Switzerland. [email protected].
¹² International Cancer Prevention Institute, Epalinges, 1066, Switzerland. [email protected].

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Arginine* / metabolism
Cell Differentiation / genetics
Epigenome*
Histones / metabolism
Humans
Keratinocytes / metabolism
Protein Serine-Threonine Kinases / metabolism
Protein-Arginine N-Methyltransferases / metabolism
Repressor Proteins / metabolism

Substances

Arginine
Histones
Protein-Arginine N-Methyltransferases
PRMT1 protein, human
Repressor Proteins
PRMT5 protein, human
ULK3 protein, human
Protein Serine-Threonine Kinases

Abstract

Publication types

MeSH terms

Substances

Grants and funding