c-Rel regulates Ezh2 expression in activated lymphocytes and malignant lymphoid cells

Area of Science:

• Epigenetics and Gene Regulation
• Molecular Biology
• Immunology

Background:

• Polycomb group protein Ezh2 is a histone methyltransferase crucial for gene expression regulation.
• Ezh2's role in embryonic development, lymphocyte activation, and cancer is established, but its regulatory mechanisms remain unclear.
• Understanding Ezh2 regulation is vital for developing targeted therapies, especially in lymphoid malignancies.

Purpose of the Study:

• To identify key regulators of Ezh2 transcription in lymphoid cells.
• To investigate the role of c-Rel in controlling Ezh2 expression.
• To explore the therapeutic implications of targeting the c-Rel-Ezh2 axis in lymphoid cancers.

Main Methods:

• Analysis of Ezh2 mRNA expression in activated primary murine B and T cells.
• Assessment of c-Rel recruitment to the Ezh2 locus using chromatin immunoprecipitation.
• Evaluation of Ezh2 expression in c-Rel-deficient lymphocytes and following c-Rel knockdown.
• Treatment of human leukemia and multiple myeloma cell lines with c-Rel inhibitor pentoxifylline and Ezh2 inhibitor GSK126.

Main Results:

• c-Rel was identified as a critical activator of Ezh2 transcription in activated murine and human lymphoid cells.
• Recruitment of c-Rel to the Ezh2 gene locus directly promoted Ezh2 mRNA expression.
• Ezh2 up-regulation by c-Rel was dependent on c-Rel presence, as shown in c-Rel-deficient cells and knockdown experiments.
• Inhibition of c-Rel reduced Ezh2 expression and sensitized malignant lymphoid cells to Ezh2-specific drugs, increasing growth inhibition and cell death.

Conclusions:

• c-Rel is a novel and critical regulator of Ezh2 expression in lymphocytes and lymphoid malignancies.
• The c-Rel-Ezh2 regulatory axis represents a significant pathway in transformed lymphoid cells.
• Targeting the c-Rel-Ezh2 interaction offers a potential strategy for combinatorial drug therapy in lymphoid cancers.