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

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

2020-03-20

10.1080/15548627.2020.1731266

Autophagy   影响因子和分区

1554-8627

1554-8635

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.

Acetylation ATG5 dimerization ELP3 glioblastoma PAK1 phosphorylation SIRT1 ubiquitination

SCI

英语

通讯

Shanghai University of Medicine&Health Sciences Seed Fund[SFP-18-21-16-001] ; Shanghai University of Medicine&Health Sciences Seed Fund[SFP-18-20-16-006]

Cell Biology

Cell Biology

WOS:000524183100001

TAYLOR & FRANCIS INC

Web of Science

1.Guilin Med Univ, Guangxi Neurol Dis Clin Res Ctr, Guangxi Key Lab Brain & Cognit Neurosci, Affiliated Hosp, Guilin, Guangxi, Peoples R China
2.Yale Univ, Sch Med, Dept Immunobiol, New Haven, CT USA
3.Cent South Univ, Xiang Ya Sch Med, Dept Histol & Embryol, Changsha, Peoples R China
4.Beijing Hosp, Natl Ctr Gerontol, Neurol Dept, Beijing, Peoples R China
5.Shanghai Univ Med & Hlth Sci, Dept Cardiol, Jiading Dist Cent Hosp, Shanghai, Peoples R China
6.Harbin Med Univ, Dept Oncol, Affiliated Hosp 3, Harbin, Peoples R China
7.Rutgers State Univ, Rutgers Canc Inst New Jersey, New Brunswick, NJ USA
8.First Hosp Jilin Univ, Dept Radiat Oncol, Changchun, Peoples R China
9.Jinan Univ, Southern Univ Sci & Technol, Shenzhen Peoples Hosp, Clin Med Res Ctr,Affiliated Hosp 1,Clin Med Coll, Shenzhen, Peoples R China
10.Jinan Univ, Shenzhen Peoples Hosp, Shenzhen Publ Serv Platform Tumor Precis Med & Mo, Clin Med Coll 2, Shenzhen, Peoples R China
11.Guilin Med Univ, Dept Neurol, Affiliated Hosp, Guilin, Guangxi, Peoples R China
12.Beijing Neurosurg Inst, Beijing, Peoples R China
13.Rutgers State Univ, Robert Wood Johnson Med Sch, Dept Surg, Univ Hosp, New Brunswick, NJ 08854 USA

Feng, Xing,Zhang, Heng,Meng, Lingbing,et al. Hypoxia-induced acetylation of PAK1 enhances autophagy and promotes brain tumorigenesis via phosphorylating ATG5[J]. Autophagy,2020,17(3).

Feng, Xing.,Zhang, Heng.,Meng, Lingbing.,Song, Huiwen.,Zhou, Qingxin.,...&Zhang, Zhiyong.(2020).Hypoxia-induced acetylation of PAK1 enhances autophagy and promotes brain tumorigenesis via phosphorylating ATG5.Autophagy,17(3).

Feng, Xing,et al."Hypoxia-induced acetylation of PAK1 enhances autophagy and promotes brain tumorigenesis via phosphorylating ATG5".Autophagy 17.3(2020).