Polycomb repressor complex-2 is a novel target for mesothelioma therapy

Area of Science:

• Epigenetics
• Oncology

Background:

• Polycomb group (PcG) proteins regulate stem cell pluripotency and are implicated in cancer pathogenesis.
• Malignant pleural mesothelioma (MPM) is an aggressive cancer with limited therapeutic options.

Purpose of the Study:

• To investigate the expression and clinical significance of PcG proteins in MPM.
• To evaluate the therapeutic potential of targeting PcG proteins in MPM.

Main Methods:

• Examined PcG protein expression using microarray, qRT-PCR, immunoblot, and immunohistochemistry in MPM cell lines and patient specimens.
• Utilized lentiviral short hairpin RNA to inhibit EZH2 and EED expression and assessed the impact on MPM cell proliferation, migration, clonogenicity, and tumorigenicity.
• Investigated gene expression profiles following inhibition of EZH2, EED, or treatment with 3-deazaneplanocin A (DZNep).

Main Results:

• EZH2 and EED, components of polycomb repressor complex-2 (PRC-2), were overexpressed in MPM compared to normal mesothelial cells.
• EZH2 overexpression in ~85% of MPMs correlated with reduced patient survival and decreased miR-101/miR-26a levels.
• Inhibition of EZH2/EED or DZNep treatment reduced H3K27Me3 levels and significantly impaired MPM cell proliferation, migration, clonogenicity, and tumorigenicity.

Conclusions:

• Pharmacologic inhibition of PRC-2 represents a novel therapeutic strategy for mesothelioma.
• Targeting PcG proteins, particularly EZH2, demonstrates significant anti-tumor effects in MPM.