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Hypoxia-induced acetylation of PAK1 enhances autophagy and promotes brain tumorigenesis via phosphorylating ATG5.

Authors
  • Feng, Xing1, 2
  • Zhang, Heng3
  • Meng, Lingbing4
  • Song, Huiwen5
  • Zhou, Qingxin6, 7
  • Qu, Chao8
  • Zhao, Pan9, 10
  • Li, Qinghua11
  • Zou, Chang9, 10
  • Liu, Xing12
  • Zhang, Zhiyong1, 13
  • 1 The Affiliated Hospital of Guilin Medical University, Guangxi Key Laboratory of Brain and Cognitive Neuroscience, Guangxi Neurological Diseases Clinical Research Center, Guilin, Guangxi, China. , (China)
  • 2 Department of Immunobiology, Yale University School of Medicine, New Haven, CT, USA.
  • 3 Department of Histology and Embryology, Xiang Ya School of Medicine, Central South University, Changsha, China. , (China)
  • 4 Neurology Department, Beijing Hospital, National Center of Gerontology, Beijing.
  • 5 Department of Cardiology, Jiading District Central Hospital Affiliated Shanghai University of Medicine & Health Sciences, Shanghai, China. , (China)
  • 6 Department of Oncology, The Third Affiliated Hospital of Harbin Medical University, Harbin, China. , (China)
  • 7 Rutgers Cancer Institute of New Jersey, Rutgers University, New Brunswick, NJ, USA. , (Jersey)
  • 8 Department of Radiation Oncology, The First Hospital of Jilin University, Changchun, China. , (China)
  • 9 Clinical Medical Research Center, the First Affiliated Hospital of Southern University of Science and Technology, the Second Clinical Medical College of Jinan University, Shenzhen People's Hospital, Shenzhen, China. , (China)
  • 10 Shenzhen Public Service Platform on Tumor Precision Medicine and Molecular Diagnosis, The Second Clinical Medical College of Jinan University, Shenzhen People's Hospital, Shenzhen, China. , (China)
  • 11 Department of Neurology, the affiliated hospital of Guilin Medical University, Guangxi, China. , (China)
  • 12 Beijing Neurosurgical Institute, Beijing, China. , (China)
  • 13 Department of Surgery, Robert-Wood-Johnson Medical School University Hospital, Rutgers University, New Brunswick, New Jersey, USA. , (Jersey)
Type
Published Article
Journal
Autophagy
Publisher
Landes Bioscience
Publication Date
Mar 01, 2021
Volume
17
Issue
3
Pages
723–742
Identifiers
DOI: 10.1080/15548627.2020.1731266
PMID: 32186433
Source
Medline
Keywords
Language
English
License
Unknown

Abstract

Although the treatment of brain tumors by targeting kinase-regulated macroautophagy/autophagy, is under investigation, the precise mechanism underlying autophagy initiation and its significance in glioblastoma (GBM) remains to be defined. Here, we report that PAK1 (p21 [RAC1] activated kinase 1) is significantly upregulated and promotes GBM development. The Cancer Genome Atlas analysis suggests that the oncogenic role of PAK1 in GBM is mainly associated with autophagy. Subsequent experiments demonstrate that PAK1 indeed serves as a positive modulator for hypoxia-induced autophagy in GBM. Mechanistically, hypoxia induces ELP3-mediated PAK1 acetylation at K420, which suppresses the dimerization of PAK1 and enhances its activity, thereby leading to subsequent PAK1-mediated ATG5 (autophagy related 5) phosphorylation at the T101 residue. This event not only protects ATG5 from ubiquitination-dependent degradation but also increases the affinity between the ATG12-ATG5 complex and ATG16L1 (autophagy related 16 like 1). Consequently, ELP3-dependent PAK1 (K420) acetylation and PAK1-mediated ATG5 (T101) phosphorylation are required for hypoxia-induced autophagy and brain tumorigenesis by promoting autophagosome formation. Silencing PAK1 with shRNA or small molecule inhibitor FRAX597 potentially blocks autophagy and GBM growth. Furthermore, SIRT1-mediated PAK1-deacetylation at K420 hinders autophagy and GBM growth. Clinically, the levels of PAK1 (K420) acetylation significantly correlate with the expression of ATG5 (T101) phosphorylation in GBM patients. Together, this report uncovers that the acetylation modification and kinase activity of PAK1 plays an instrumental role in hypoxia-induced autophagy initiation and maintaining GBM growth. Therefore, PAK1 and its regulator in the autophagy pathway might represent potential therapeutic targets for GBM treatment.Abbreviations: 3-MA: 3-methyladenine; Ac-CoA: acetyl coenzyme A; ATG5: autophagy related 5; ATG16L1, autophagy related 16 like 1; BafA1: bafilomycin A1; CDC42: cell division cycle 42; CGGA: Chinese Glioma Genome Atlas; CHX, cycloheximide; ELP3: elongator acetyltransferase complex subunit 3; GBM, glioblastoma; HBSS: Hanks balanced salts solution; MAP1LC3B/LC3: microtubule associated protein 1 light chain 3 beta; MAP2K1: mitogen-activated protein kinase kinase 1; MAPK14, mitogen-activated protein kinase 14; PAK1: p21 (RAC1) activated kinase 1; PDK1: pyruvate dehydrogenase kinase 1; PGK1, phosphoglycerate kinase 1; PTMs: post-translational modifications; RAC1: Rac family small GTPase 1; SQSTM1: sequestosome 1; TCGA, The Cancer Genome Atlas.

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