Jmjd2c maintains the ALDH^bri+ cancer stemness with transcription factor SOX2 in lung squamous cell carcinoma

Area of Science:

• Oncology
• Epigenetics
• Cancer Stem Cell Biology

Background:

• Lung squamous cell carcinoma (LSCC) is a significant global health challenge.
• The role of histone demethylase Jmjd2c in LSCC pathogenesis, particularly its interaction with cancer stem cells (CSCs), remains largely undefined.
• Aldehyde dehydrogenase-bright (ALDH^bri+) cells represent a key CSC subtype in LSCC.

Purpose of the Study:

• To elucidate the molecular mechanism of Jmjd2c in regulating ALDH^bri+ CSCs in LSCC.
• To investigate the interaction between Jmjd2c and the transcription factor SOX2 in LSCC progression.
• To evaluate the therapeutic potential of targeting Jmjd2c and SOX2 in LSCC.

Main Methods:

• Utilized ALDH^bri+ LSCC cells to assess sphere formation and CSC proportion under Jmjd2c interference and caffeic acid treatment.
• Conducted bioinformatic analysis, western blotting, qRT-PCR, Co-immunoprecipitation (Co-IP), and GST pull-down assays.
• Generated Jmjd2c-silenced and Jmjd2c-SOX2-silenced tumor-bearing mice models.

Main Results:

• Jmjd2c downregulation significantly inhibited sphere formation and reduced the ALDH^bri+ CSC population.
• Jmjd2c interference led to decreased SOX2 expression, with evidence of positive co-expression and direct protein interaction between Jmjd2c and SOX2.
• Combined Jmjd2c and SOX2 silencing demonstrated a more potent inhibitory effect on tumor progression compared to Jmjd2c silencing alone.
• Jmjd2c and SOX2 expression levels correlated with LSCC patient prognosis.

Conclusions:

• Jmjd2c plays a critical role in maintaining ALDH^bri+ CSC activity in LSCC through its interaction with SOX2.
• Targeting the Jmjd2c-SOX2 axis presents a promising therapeutic strategy for LSCC.
• Jmjd2c and SOX2 may serve as valuable biomarkers for LSCC diagnosis and clinical treatment.