Targeting the histone demethylase PHF8-mediated PKC?-Src-PTEN axis in HER2-negative gastric cancer.

ABSTRACT: Targeted treatments for advanced gastric cancer (GC) are needed, particularly for HER2-negative GC, which represents the majority of cases (80 to 88%). In this study, in silico analyses of the lysine histone demethylases (KDMs) involved in diverse biological processes and diseases revealed that PHD finger protein 8 (PHF8, KDM7B) was significantly associated with poor clinical outcome in HER2-negative GC. The depletion of PHF8 significantly reduced cancer progression in GC cells and in mouse xenografts. PHF8 regulated genes involved in cell migration/motility based on a microarray analysis. Of note, PHF8 interacted with c-Jun on the promoter of PRKCA which encodes PKC?. The depletion of PHF8 or PKC? greatly up-regulated PTEN expression, which could be rescued by ectopic expression of a PKC? expression vector or an active Src. These suggest that PTEN destabilization occurs mainly via the PKC?-Src axis. GC cells treated with midostaurin or bosutinib significantly suppressed migration in vitro and in zebrafish models. Immunohistochemical analyses of PHF8, PKC?, and PTEN showed a positive correlation between PHF8 and PKC? but negative correlations between PHF8 and PTEN and between PKC? and PTEN. Moreover, high PHF8-PKC? expression was significantly correlated with worse prognosis. Together, our results suggest that the PKC?-Src-PTEN pathway regulated by PHF8/c-Jun is a potential prognostic/therapeutic target in HER2-negative advanced GC.

SUBMITTER: Tseng LL 

PROVIDER: S-EPMC7547212 | biostudies-literature | 2020 Oct

REPOSITORIES: biostudies-literature