Targeting The Histone Demethylase Phf8-Mediated Pkc Alpha-Src-Pten Axis In Her2-Negative Gastric Cancer

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 pro-cesses 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 micro array analysis. Of note, PHF8 interacted with c-Jun on the promoter of PRKCA which encodes PKC alpha. The depletion of PHF8 or PKC alpha greatly up-regulated PTEN expression, which could be rescued by ectopic expression of a PKC alpha expression vector or an active Src. These suggest that PTEN destabilization occurs mainly via the PKC alpha-Src axis. GC cells treated with midostaurin or bosutinib significantly suppressed migration in vitro and in zebrafish models. Immunohistochemical analyses of PHF8, PKC alpha, and PTEN showed a positive correlation between PHF8 and PKC alpha but negative correlations between PHF8 and PTEN and between PKC alpha and PTEN. Moreover, high PHF8-PKC alpha expression was significantly correlated with worse prognosis. Together, our results suggest that the PKC alpha-Src-PTEN pathway regulated by PHF8/c-Jun is a potential prognostic/therapeutic target in HER2-negative advanced GC. treatment ferential gene genes, and targeted tions, from tribute epigenetic expression