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Nat Cell Biol. 2019 Feb;21(2):226-237. doi: 10.1038/s41556-018-0261-6. Epub 2019 Jan 28.

AKT methylation by SETDB1 promotes AKT kinase activity and oncogenic functions.

Author information

1
The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.
2
Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.
3
Institute of Translational Medicine, The First Hospital, Jilin University, Changchun, China.
4
Division of Newborn Medicine and Epigenetics Program, Department of Medicine, Boston Children's Hospital, Boston, MA, USA.
5
Key Laboratory of Systems Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Science, Shanghai, China.
6
Cell Signaling Technology Inc., Danvers, MA, USA.
7
Division of Signal Transduction, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.
8
Department of Biochemistry and Biophysics, Lineberger Comprehensive Cancer Center, The University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
9
Division of Genetics, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.
10
Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA. wwei2@bidmc.harvard.edu.

Abstract

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.

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PMID:
30692625
PMCID:
PMC6377565
DOI:
10.1038/s41556-018-0261-6
[Indexed for MEDLINE]
Free PMC Article

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