Autopalmitoylation of IDH1-R132H regulates its neomorphic activity in cancer cells.

Lu Hu¹, Jinyu Lin², Liping Sun², Alison M Berezuk³, Katharine S Tuttle³, Xing Zhu³, Hyuk-Soo Seo^4,5, Sirano Dhe-Paganon^4,5, Pan Li⁶, Yang Sun^7,6, Lisheng Ni⁸, Jianan Zhang⁷, Dazhi Tan⁹, Hiroaki Wakimoto¹⁰, Daniel P Cahill¹⁰, Xiaochen Bai⁸, Xuelian Luo⁸, John M Asara¹¹, Sriram Subramaniam³, Yibing Shan^12,13, Xu Wu¹⁴

¹Cutaneous Biology Research Center, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA, USA. lhu8@mgh.harvard.edu.

²iHuman Institute, Shanghai Tech University, Shanghai, China.

³Department of Biochemistry & Molecular Biology, University of British Columbia, Vancouver, British Columbia, Canada.

⁴Department of Biological Chemistry & Molecular Pharmacology, Harvard Medical School, Boston, MA, USA.

⁵Chemical Biology Program, Dana-Farber Cancer Institute, Boston, MA, USA.

⁶Cancer Institute, Xuzhou Medical University, Xuzhou, China.

⁷Cutaneous Biology Research Center, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA, USA.

⁸Department of Biophysics, University of Texas Southwestern Medical Center, Dallas, TX, USA.

⁹Antidote Health Foundation for Cure of Cancer, Cambridge, MA, USA.

¹⁰Department of Neurosurgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.

¹¹Mass Spectrometry Core, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.

¹²iHuman Institute, Shanghai Tech University, Shanghai, China. shanyb@shanghaitech.edu.cn.

¹³Antidote Health Foundation for Cure of Cancer, Cambridge, MA, USA. shanyb@shanghaitech.edu.cn.

¹⁴Cutaneous Biology Research Center, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA, USA. xuwu@mgh.harvard.edu.

PubMed DOI

Abstract

Gain-of-function mutations of isocitrate dehydrogenase 1 (IDH1) lead to oncometabolite (R)-2-hydroxyglutarate production, contributing to the tumorigenesis of multiple human cancers. While fatty acid biosynthesis is critical for IDH1-mutant tumor growth, the underlying mechanisms remain unclear. Here, leveraging chemical probes and chemoproteomic profiling, we identified that oncogenic IDH1-R132H…

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