SETDB1-mediated methylation of Akt promotes its K63-linked ubiquitination and activation leading to tumorigenesis

Guihua Wang, Jie Long, Yuan Gao, Weina Zhang, Fei Han, Chuan Xu, Li Sun, Shun Chin Yang, Jingqin Lan, Zhenlin Hou, Zhen Cai, Guoxiang Jin, Che Chia Hsu, Yu Hui Wang, Junbo Hu, Tsai Yu Chen, Hongyu Li, Min Gyu Lee, Hui Kuan Lin

Research output: Contribution to journalArticle

31 Scopus citations

Abstract

The serine/threonine kinase Akt plays a central role in cell proliferation, survival and metabolism, and its hyperactivation is linked to cancer progression. Here we report that Akt undergoes K64 methylation by SETDB1, which is crucial for cell membrane recruitment, phosphorylation and activation of Akt following growth factor stimulation. Furthermore, we reveal an adaptor function of histone demethylase JMJD2A, which is important for recognizing Akt K64 methylation and recruits E3 ligase TRAF6 and Skp2-SCF to the Akt complex, independently of its demethylase activity, thereby initiating K63-linked ubiquitination, cell membrane recruitment and activation of Akt. Notably, the cancer-associated Akt mutant E17K displays enhanced K64 methylation, leading to its hyper-phosphorylation and activation. SETDB1-mediated Akt K64 methylation is upregulated and correlated with Akt hyperactivation in non-small-cell lung carcinoma (NSCLC), promotes tumour development and predicts poor outcome. Collectively, these findings reveal complicated layers of Akt activation regulation coordinated by SETDB1-mediated Akt K64 methylation to drive tumorigenesis.

Original languageEnglish (US)
Pages (from-to)214-225
Number of pages12
JournalNature Cell Biology
Volume21
Issue number2
DOIs
StatePublished - Feb 1 2019

ASJC Scopus subject areas

  • Cell Biology

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    Wang, G., Long, J., Gao, Y., Zhang, W., Han, F., Xu, C., Sun, L., Yang, S. C., Lan, J., Hou, Z., Cai, Z., Jin, G., Hsu, C. C., Wang, Y. H., Hu, J., Chen, T. Y., Li, H., Lee, M. G., & Lin, H. K. (2019). SETDB1-mediated methylation of Akt promotes its K63-linked ubiquitination and activation leading to tumorigenesis. Nature Cell Biology, 21(2), 214-225. https://doi.org/10.1038/s41556-018-0266-1