Targeting the histone demethylase PHF8-mediated PKCα-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 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 The depletion of PHF8 or greatly up-regulated PTEN expression, which could be rescued by ectopic expression of a duanyu1531α expression vector or an active Src. These suggest that PTEN destabilization occurs mainly via the axis. GC cells treated with midostaurin or bosutinib significantly suppressed migration in vitro and in zebrafish models. Immunohistochemical analyses of PHF8, and PTEN showed a positive correlation between PHF8 and duanyu1531α but negative correlations between PHF8 and PTEN and between duanyu1531α and PTEN. Moreover, high expression was significantly correlated with worse prognosis. Together, our results suggest that the pathway regulated by PHF8/c-Jun is a potential prognostic/therapeutic target in HER2-negative advanced GC.

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