A PRC2-independent function for EZH2 in regulating rRNA 2'-O methylation and IRES-dependent translation

Area of Science:

• Molecular Biology
• Cancer Research
• Epigenetics

Background:

• Dysregulated translation is a hallmark of cancer, making its regulatory mechanisms critical therapeutic targets.
• Enhancer of zeste homologue 2 (EZH2) is known for its role as a transcriptional repressor and lysine methyltransferase.
• Understanding novel functions of EZH2 is crucial for developing targeted cancer therapies.

Purpose of the Study:

• To investigate the role of enhancer of zeste homologue 2 (EZH2) in translational regulation within cancer cells.
• To elucidate the mechanism by which EZH2 influences translation.
• To identify potential new therapeutic targets by uncovering EZH2's non-transcriptional functions.

Main Methods:

• Co-immunoprecipitation assays to detect protein-protein interactions between EZH2 and fibrillarin (FBL).
• Analysis of rRNA 2'-O methylation levels in cells with varying EZH2 expression.
• Assessment of global and internal ribosome entry site (IRES)-dependent translation initiation rates.
• Investigating the impact of EZH2 deficiency on the assembly of the box C/D small nucleolar ribonucleoprotein complex.

Main Results:

• EZH2 directly interacts with fibrillarin (FBL), revealing a novel role in translational control.
• EZH2 enhances rRNA 2'-O methylation through its interaction with FBL.
• EZH2 facilitates the assembly of the box C/D small nucleolar ribonucleoprotein complex by strengthening the FBL-NOP56 interaction.
• EZH2 deficiency leads to impaired global translation and reduced IRES-dependent translation initiation in cancer cells.

Conclusions:

• EZH2 plays a significant, previously unrecognized role in regulating translation in cancer.
• The interaction between EZH2 and FBL is critical for rRNA methylation and subsequent translational control.
• Targeting EZH2's role in translation may offer novel therapeutic strategies for cancer treatment.