AMPK Phosphorylates ZDHHC13 to Increase MC1R Activity and Suppress Melanomagenesis.
Journal
Cancer research
ISSN: 1538-7445
Titre abrégé: Cancer Res
Pays: United States
ID NLM: 2984705R
Informations de publication
Date de publication:
04 04 2023
04 04 2023
Historique:
received:
16
08
2022
revised:
22
12
2022
accepted:
24
01
2023
medline:
5
4
2023
pubmed:
27
1
2023
entrez:
26
1
2023
Statut:
ppublish
Résumé
Inherited genetic variations in the melanocortin-1 receptor (MC1R) responsible for human red hair color (RHC) variants are associated with impaired DNA damage repair and increased melanoma risk. MC1R signaling is critically dependent on palmitoylation, primarily mediated by the protein acyltransferase zinc finger DHHC-type palmitoyltransferase 13 (ZDHHC13). A better understanding of how ZDHHC13 is physiologically activated could help identify approaches to prevent melanomagenesis in redheads. Here, we report that AMP-activated protein kinase (AMPK) phosphorylates ZDHHC13 at S208 to strengthen the interaction between ZDHHC13 and MC1R-RHC, leading to enhanced MC1R palmitoylation in redheads. Consequently, phosphorylation of ZDHHC13 by AMPK increased MC1R-RHC downstream signaling. AMPK activation and MC1R palmitoylation repressed UVB-induced transformation of human melanocytes in vitro and delayed melanomagenesis in vivo in C57BL/6J-MC1R-RHC mice. The importance of AMPK to MC1R signaling was validated in human melanomas where AMPK upregulation correlated with expression of factors downstream from MC1R signaling and with prolonged patient survival. These findings suggest AMPK activation as a promising strategy to reduce melanoma risk, especially for individuals with red hair. Phosphorylation of ZDHHC13 by AMPK at S208 promotes MC1R activation and suppresses melanocyte transformation, indicating activation of AMPK as a potential approach to prevent melanoma in people with red hair.
Identifiants
pubmed: 36701140
pii: 716224
doi: 10.1158/0008-5472.CAN-22-2595
pmc: PMC10073341
mid: NIHMS1870920
doi:
Substances chimiques
AMP-Activated Protein Kinases
EC 2.7.11.31
ZDHHC13 protein, human
EC 2.3.1.-
MC1R protein, human
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1062-1073Subventions
Organisme : NCI NIH HHS
ID : R00 CA234097
Pays : United States
Organisme : NCI NIH HHS
ID : K99 CA234097
Pays : United States
Informations de copyright
©2023 American Association for Cancer Research.
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