Targeting the histone demethylase PHF8-mediated PKCα-Src-PTEN axis in HER2-negative gastric cancer

Lin Lu Tseng, Hsin Hung Cheng, Ta Sen Yeh, Shih Chiang Huang, Ya Yun Syu, Chih Pin Chuu, Chiou Hwa Yuh, Hsing Jien Kung, Wen Ching Wang

Research output: Contribution to journalArticlepeer-review

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

Original languageEnglish (US)
Pages (from-to)24859-24866
Number of pages8
JournalProceedings of the National Academy of Sciences of the United States of America
Volume117
Issue number40
DOIs
StatePublished - Oct 6 2020

Keywords

  • HER2-negative gastric cancer
  • histone lysine demethylase
  • PHF8
  • PKCα
  • PTEN

ASJC Scopus subject areas

  • General

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