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

Area of Science:

• Oncology
• Molecular Biology
• Cancer Research

Background:

• Advanced gastric cancer (GC) lacks targeted treatments, especially for HER2-negative subtypes (80-88% of cases).
• Lysine histone demethylases (KDMs) play roles in various diseases, necessitating investigation in GC.
• PHD finger protein 8 (PHF8) emerged as a potential factor in GC progression.

Purpose of the Study:

• To investigate the role of PHF8 in HER2-negative advanced GC.
• To identify PHF8-regulated pathways involved in GC progression.
• To evaluate PHF8 and associated molecules as potential therapeutic targets.

Main Methods:

• In silico analysis of KDMs in GC.
• PHF8 depletion in GC cell lines and mouse xenografts.
• Microarray analysis of PHF8-regulated genes.
• Investigation of PHF8 interaction with c-Jun and the PKCα-Src-PTEN axis.
• Treatment of GC cells with midostaurin or bosutinib.
• Immunohistochemical analysis of PHF8, PKCα, and PTEN in patient samples.

Main Results:

• PHF8 depletion significantly reduced GC progression in vitro and in vivo.
• PHF8 regulates genes involved in cell migration and motility.
• PHF8 interacts with c-Jun to regulate PKCα, influencing PTEN stability via the PKCα-Src axis.
• PHF8 and PKCα expression positively correlated, while PHF8/PKCα negatively correlated with PTEN.
• High PHF8-PKCα expression correlated with poor prognosis in HER2-negative GC patients.
• Midostaurin and bosutinib suppressed GC cell migration.

Conclusions:

• The PHF8/c-Jun complex regulates the PKCα-Src-PTEN pathway, crucial for HER2-negative advanced GC progression.
• PHF8 and the PKCα-Src-PTEN pathway represent potential prognostic and therapeutic targets for HER2-negative advanced GC.