AKT methylation by SETDB1 promotes AKT kinase activity and oncogenic functions

• Published in: Nature cell biology Vol. 21; no. 2; pp. 226 - 237
• Main Authors: Guo, Jianping, Dai, Xiangpeng, Laurent, Benoit, Zheng, Nana, Gan, Wenjian, Zhang, Jian, Guo, Ailan, Yuan, Min, Liu, Pengda, Asara, John M., Toker, Alex, Shi, Yang, Pandolfi, Pier Paolo, Wei, Wenyi
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.02.2019; Nature Publishing Group
• Subjects: 1-Phosphatidylinositol 3-kinase; 13/1; 13/106; 13/109; 13/31; 13/51; 13/95; 38/23; 38/70; 631/67; 631/80/458/1648; 631/80/458/582; 631/80/86/2368; 64/60; 82/29; 82/58; 96/63; Activation; AKT protein; AKT1 protein; Animals; Antibiotics, Antineoplastic - pharmacology; Biomedical and Life Sciences; Body size; Cancer; Cancer Research; Carcinogenesis; Carcinogenesis - genetics; Carcinogenesis - metabolism; Carcinogens; Cell Biology; Cell Line, Tumor; Developmental Biology; Female; Health aspects; HEK293 Cells; Histone-Lysine N-Methyltransferase; Homeostasis; Humans; Kinases; Life Sciences; Lysine; Methylation; Methyltransferases; Mice; Mice, Nude; Mice, Transgenic; Neoplasms - drug therapy; Neoplasms - genetics; Neoplasms - metabolism; Phosphatidylinositol; Phospholipids; Phosphorylation; Physiological aspects; Plicamycin - pharmacology; Protein kinases; Protein Methyltransferases - genetics; Protein Methyltransferases - metabolism; Protein-Serine-Threonine Kinases - genetics; Protein-Serine-Threonine Kinases - metabolism; Proto-Oncogene Proteins c-akt - genetics; Proto-Oncogene Proteins c-akt - metabolism; Sf9 Cells; Signal transduction; Signaling; Skin; Spodoptera; Stem Cells; Transferases; Tumors; Xenograft Model Antitumor Assays - methods
• ISSN: 1465-7392; 1476-4679
• DOI: 10.1038/s41556-018-0261-6

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. Guo et al. identify SETDB1 and KDM4B as the methyltransferase and demethylase, respectively, for AKT. AKT methylation promotes its kinase activity and the subsequent tumorigenesis.