EZH2 regulates a SETDB1/ΔNp63α axis via RUNX3 to drive a cancer stem cell phenotype in squamous cell carcinoma

Area of Science:

• Epigenetics
• Cancer Biology
• Molecular Oncology

Background:

• Enhancer of zeste homolog 2 (EZH2) and SET domain bifurcated 1 (SETDB1) are oncogenic methyltransferases.
• These enzymes epigenetically repress gene expression by methylating histone H3 residues.
• EZH2 targets H3 K27, while SETDB1 targets H3-K9.

Purpose of the Study:

• To investigate the role of EZH2 and SETDB1 in squamous cell carcinoma (SCC) stem cell proliferation and aggressiveness.
• To elucidate the molecular pathway involving EZH2, SETDB1, and ΔNp63α in SCC.
• To explore the therapeutic potential of targeting this pathway.

Main Methods:

• Depletion of EZH2 and SETDB1 in SCC cell lines (HSC-5, FaDu, Cal33).
• Analysis of stem-like cell phenotypes (spheroid formation, invasion, tumor growth).
• Investigation of protein-protein interactions and regulatory mechanisms using molecular biology techniques.
• Pharmacological inhibition of EZH2.

Main Results:

• EZH2 and SETDB1 are essential for SCC cell proliferation and highly expressed in aggressive stem-like SCC subpopulations.
• Depletion of EZH2 or SETDB1 disrupts SCC stem-like cells and their associated aggressive phenotypes.
• SETDB1 cooperates with ΔNp63α to regulate SCC stem cell phenotype.
• EZH2 acts upstream, repressing RUNX3 to activate SETDB1 and ΔNp63α.
• EZH2 inhibition activates RUNX3 and represses SETDB1 and ΔNp63α, antagonizing the SCC stem cell phenotype.

Conclusions:

• A novel pathway involving EZH2, SETDB1, and ΔNp63α drives aggressive SCC stem cell phenotypes.
• EZH2 plays a critical upstream role in regulating this oncogenic pathway.
• Targeting EZH2 with inhibitors presents a promising pharmacological intervention for SCC.