EZH2 Inhibition Restores Tumor Suppressor SFRP1 Activity by Reprogramming Extrachromosomal Circular DNA Dynamics in...

Area of Science:

• Oncology
• Epigenetics
• Genomics

Background:

• Extrachromosomal circular DNA (eccDNA) drives cancer progression, oncogene amplification, and tumor heterogeneity.
• The interaction between eccDNA and epigenetic regulators like EZH2 is poorly understood in cancer.

Purpose of the Study:

• To investigate the impact of the EZH2 inhibitor Tazemetostat on eccDNA landscape and gene expression in ovarian cancer.
• To explore the novel epigenetic-eccDNA axis in cancer plasticity and therapeutic resistance.

Main Methods:

• Utilized Circle-seq and RNA sequencing for integrated profiling.
• Employed multi-omics integration to identify concordant gene changes.
• Applied spatial single-cell transcriptomics to analyze gene expression patterns.

Main Results:

• EZH2 inhibition significantly altered eccDNA dynamics and transcriptional programs.
• Identified 67 genes with concordant changes in eccDNA abundance and transcript expression.
• SFRP1 was consistently reactivated as a tumor suppressor by Tazemetostat across multiple datasets.

Conclusions:

• EZH2 inhibition may reprogram eccDNA dynamics to restore SFRP1 tumor suppressor expression in ovarian cancer.
• A novel epigenetic-eccDNA axis was uncovered, potentially impacting oncogenic plasticity and therapeutic resistance.
• This finding could shift paradigms in targeting eccDNA-driven cancers.