AKT methylation by SETDB1 promotes AKT kinase activity and oncogenic functions.
Animals
Antibiotics, Antineoplastic
/ pharmacology
Carcinogenesis
/ genetics
Cell Line, Tumor
Female
HEK293 Cells
Histone-Lysine N-Methyltransferase
Humans
Methylation
Mice, Nude
Mice, Transgenic
Neoplasms
/ drug therapy
Plicamycin
/ pharmacology
Protein Methyltransferases
/ genetics
Protein Serine-Threonine Kinases
/ genetics
Proto-Oncogene Proteins c-akt
/ genetics
Sf9 Cells
Spodoptera
Xenograft Model Antitumor Assays
/ methods
Journal
Nature cell biology
ISSN: 1476-4679
Titre abrégé: Nat Cell Biol
Pays: England
ID NLM: 100890575
Informations de publication
Date de publication:
02 2019
02 2019
Historique:
received:
21
12
2017
accepted:
10
12
2018
pubmed:
30
1
2019
medline:
16
4
2019
entrez:
30
1
2019
Statut:
ppublish
Résumé
Aberrant activation of AKT disturbs the proliferation, survival and metabolic homeostasis of various human cancers. Thus, it is critical to understand the upstream signalling pathways governing AKT activation. Here, we report that AKT undergoes SETDB1-mediated lysine methylation to promote its activation, which is antagonized by the Jumonji-family demethylase KDM4B. Notably, compared with wild-type mice, mice harbouring non-methylated mutant Akt1 not only exhibited reduced body size but were also less prone to carcinogen-induced skin tumours, in part due to reduced AKT activation. Mechanistically, the interaction of phosphatidylinositol (3,4,5)-trisphosphate with AKT facilitates its interaction with SETDB1 for subsequent AKT methylation, which in turn sustains AKT phosphorylation. Pathologically, genetic alterations, including SETDB1 amplification, aberrantly promote AKT methylation to facilitate its activation and oncogenic functions. Thus, AKT methylation is an important step, synergizing with PI3K signalling to control AKT activation. This suggests that targeting SETDB1 signalling could be a potential therapeutic strategy for combatting hyperactive AKT-driven cancers.
Identifiants
pubmed: 30692625
doi: 10.1038/s41556-018-0261-6
pii: 10.1038/s41556-018-0261-6
pmc: PMC6377565
mid: NIHMS1516425
doi:
Substances chimiques
Antibiotics, Antineoplastic
0
Protein Methyltransferases
EC 2.1.1.-
Histone-Lysine N-Methyltransferase
EC 2.1.1.43
SETDB1 protein, human
EC 2.1.1.43
Protein Serine-Threonine Kinases
EC 2.7.11.1
Proto-Oncogene Proteins c-akt
EC 2.7.11.1
Plicamycin
NIJ123W41V
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
226-237Subventions
Organisme : NCI NIH HHS
ID : R01 CA177910
Pays : United States
Organisme : NIGMS NIH HHS
ID : R01 GM089763
Pays : United States
Organisme : NCI NIH HHS
ID : P30 CA006516
Pays : United States
Organisme : NCI NIH HHS
ID : P01 CA120964
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA200573
Pays : United States
Organisme : NCI NIH HHS
ID : K99 CA207867
Pays : United States
Organisme : NCI NIH HHS
ID : R00 CA207867
Pays : United States
Commentaires et corrections
Type : CommentIn
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