title: PCAF acts as a gastric cancer suppressor through a novel PCAF-p16-CDK4 axis.
abstract: Gastric cancer (GC) is a leading cause of cancer-related death worldwide and the pathogenesis of GC remains largely unknown. Here, we demonstrate a novel mechanism by which P300/CBP associating factor (PCAF) acts as a tumor suppressor in GC cells. We showed that both PCAF mRNA and protein were downregulated in GC cells, and that this downregulation correlated with poor survival. Meanwhile, the interaction between human anion exchanger 1 (AE1) and p16 is a key event in GC development. We found that PCAF inhibited GC growth by interacting with AE1 and p16 to promote ubiquitin-mediated degradation of AE1 and p16 upregulation and translocation into the nucleus. Binding of nuclear p16 to CDK4 prevented the CDK4-Cyclin D1 interaction to inhibit GC proliferation. Furthermore, reduced PCAF levels in GC cells were associated with intracellular alkalinization and decreased immunity. Together these results suggest that PCAF acts as a GC suppressor through a novel PCAF-p16-CDK4 axis. The downregulation of PCAF expression in GC cells that follows intracellular alkalinization and decreased immune response, indicates that GC therapies should focus on restoring PCAF levels.
authors.affiliation: Pathology Center, Shanghai General Hospital/Faculty of Basic Medicine, School of Medicine, Shanghai Jiao Tong University Shanghai 200025, P. R. China.
authors.forename: Hong-Jun
authors.initials: HJ
authors.lastname: Fei
authors.affiliation: Pathology Center, Shanghai General Hospital/Faculty of Basic Medicine, School of Medicine, Shanghai Jiao Tong University Shanghai 200025, P. R. China.
authors.forename: Li-Dong
authors.initials: LD
authors.lastname: Zu
authors.affiliation: Pathology Center, Shanghai General Hospital/Faculty of Basic Medicine, School of Medicine, Shanghai Jiao Tong University Shanghai 200025, P. R. China.
authors.forename: Jun
authors.initials: J
authors.lastname: Wu
authors.affiliation: Department of Pathophysiology, Harbin Medical University Harbin 150081, P. R. China.
authors.forename: Xiao-Shu
authors.initials: XS
authors.lastname: Jiang
authors.affiliation: Pathology Center, Shanghai General Hospital/Faculty of Basic Medicine, School of Medicine, Shanghai Jiao Tong University Shanghai 200025, P. R. China.
authors.forename: Jing-Long
authors.initials: JL
authors.lastname: Wang
authors.affiliation: Institute of Health Sciences, Shanghai Institutes of Biological Sciences, Chinese Academy of Sciences Shanghai, P. R. China.
authors.forename: Y Eugene
authors.initials: YE
authors.lastname: Chin
authors.affiliation: Pathology Center, Shanghai General Hospital/Faculty of Basic Medicine, School of Medicine, Shanghai Jiao Tong University Shanghai 200025, P. R. China.
authors.forename: Guo-Hui
authors.initials: GH
authors.lastname: Fu
keywords: AE1; GC; PCAF-P16-CDK4 axis; proliferation