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

in Autophagy by Xing Feng, Heng Zhang, Lingbing Meng, Huiwen Song, Qingxin Zhou, Chao Qu, Pan Zhao, Qinghua Li, Chang Zou, Xing Liu, Zhiyong Zhang

TLDR

  • The study investigates how a protein called PAK1 affects the growth of a type of brain tumor called glioblastoma (GBM). The authors found that PAK1 is more active in GBM and helps it grow. The study suggests that PAK1 helps GBM grow by making a protein called ATG5 more active. The study also found that a protein called ELP3 helps PAK1 become more active by adding a chemical group to it. The study suggests that PAK1 and ELP3 might be potential targets for treating GBM.

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. Silencingwith 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.3-MA: 3-methyladenine; Ac-CoA: acetyl coenzyme A; ATG5: autophagy related 5; ATG16L1, autophagy related 16 like 1; BafA: bafilomycin A; 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.

Overview

  • The study investigates the role of PAK1 in glioblastoma (GBM) development and its significance in autophagy initiation. The authors report that PAK1 is significantly upregulated in GBM and promotes GBM development. The study suggests that the oncogenic role of PAK1 in GBM is mainly associated with autophagy. The authors demonstrate that PAK1 serves as a positive modulator for hypoxia-induced autophagy in GBM. The study identifies ELP3-mediated PAK1 acetylation at K420 as a key mechanism underlying autophagy initiation and its significance in GBM development. The study aims to understand the precise mechanism underlying autophagy initiation and its significance in GBM development.

Comparative Analysis & Findings

  • The study compares the outcomes observed under different experimental conditions or interventions, specifically the effects of hypoxia on autophagy initiation and its significance in GBM development. The authors identify ELP3-mediated PAK1 acetylation at K420 as a key mechanism underlying autophagy initiation and its significance in GBM development. The study demonstrates that PAK1 serves as a positive modulator for hypoxia-induced autophagy in GBM. The authors suggest that the oncogenic role of PAK1 in GBM is mainly associated with autophagy. The study identifies SIRT1-mediated PAK1-deacetylation at K420 as a key mechanism underlying autophagy initiation and its significance in GBM development.

Implications and Future Directions

  • The study's findings suggest that PAK1 and its regulator in the autophagy pathway might represent potential therapeutic targets for GBM treatment. The study identifies ELP3-mediated PAK1 acetylation at K420 as a key mechanism underlying autophagy initiation and its significance in GBM development. The study suggests that the oncogenic role of PAK1 in GBM is mainly associated with autophagy. The study identifies SIRT1-mediated PAK1-deacetylation at K420 as a key mechanism underlying autophagy initiation and its significance in GBM development. The study suggests that the acetylation modification and kinase activity of PAK1 play an instrumental role in hypoxia-induced autophagy initiation and maintaining GBM growth. The study identifies potential therapeutic targets for GBM treatment.
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