FOXM1 contributes to taxane resistance by regulating UHRF1-controlled cancer cell stemness

Area of Science:

• Oncology
• Epigenetics
• Cancer Stem Cell Biology

Background:

• Therapy-induced cancer stem cell (CSC) expansion is a key driver of therapeutic resistance.
• UHRF1 is an epigenetic regulator involved in stem cell self-renewal and therapeutic resistance.
• Mechanisms underlying CSC adaptation and therapeutic resistance require further elucidation.

Purpose of the Study:

• To investigate the role of UHRF1 in taxane resistance and CSC expansion.
• To explore the relationship between FOXM1 and UHRF1 in the context of CSCs and taxane resistance.
• To identify novel therapeutic targets for overcoming taxane resistance.

Main Methods:

• Establishment of taxane-resistant cancer cell lines with expanded stem-like properties.
• Assessment of UHRF1 and FOXM1 expression in resistant cells and prostate cancer tissues.
• In vitro and in vivo experiments to evaluate the effect of UHRF1 depletion on taxane resistance.
• Analysis of FOXM1 binding to the UHRF1 promoter and its regulatory role in gene transcription.

Main Results:

• UHRF1 was overexpressed in taxane-resistant cancer cells, correlating with CSC characteristics.
• UHRF1 depletion effectively reversed taxane resistance both in vitro and in vivo.
• FOXM1 and UHRF1 showed high correlation in prostate cancer, with FOXM1 directly regulating UHRF1 transcription.
• FOXM1 controls CSCs and taxane resistance via a UHRF1-mediated pathway.

Conclusions:

• FOXM1 regulates CSCs and taxane resistance by controlling UHRF1 transcription through direct promoter binding.
• The FOXM1-UHRF1 signaling pathway represents a novel mechanism contributing to therapeutic resistance.
• Both FOXM1 and UHRF1 are validated as potential therapeutic targets to overcome taxane resistance.