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ZFIN ID: ZDB-PUB-201002-114
Targeting the histone demethylase PHF8-mediated PKCα-Src-PTEN axis in HER2-negative gastric cancer
Tseng, L.L., Cheng, H.H., Yeh, T.S., Huang, S.C., Syu, Y.Y., Chuu, C.P., Yuh, C.H., Kung, H.J., Wang, W.C.
Date: 2020
Source: Proceedings of the National Academy of Sciences of the United States of America   117(40): 24859-24866 (Journal)
Registered Authors: Yuh, Chiou-Hwa (Cathy)
Keywords: HER2-negative gastric cancer, PHF8, PKCĪ±, PTEN, histone lysine demethylase
MeSH Terms:
  • Animals
  • Cell Line, Tumor
  • Cell Movement
  • Female
  • Gene Expression Regulation, Neoplastic
  • Histone Demethylases/genetics
  • Histone Demethylases/metabolism*
  • Humans
  • Mice
  • PTEN Phosphohydrolase/genetics
  • PTEN Phosphohydrolase/metabolism
  • Protein Kinase C-alpha/genetics
  • Protein Kinase C-alpha/metabolism*
  • Proto-Oncogene Proteins pp60(c-src)/genetics
  • Proto-Oncogene Proteins pp60(c-src)/metabolism*
  • Receptor, ErbB-2/genetics
  • Receptor, ErbB-2/metabolism
  • Stomach Neoplasms/genetics
  • Stomach Neoplasms/metabolism*
  • Stomach Neoplasms/physiopathology
  • Transcription Factors/genetics
  • Transcription Factors/metabolism*
PubMed: 32958674 Full text @ Proc. Natl. Acad. Sci. USA
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.