Targeting Excessive EZH1 and EZH2 Activities for Abnormal Histone Methylation and Transcription Network in Malignant...

Area of Science:

• Epigenetics
• Cancer Biology
• Molecular Oncology

Background:

• Global H3K27me3 reprogramming is a cancer hallmark, but effective therapies for H3K27me3-high malignancies with wild-type EZH2 (EZH2^WT/WT) are lacking.
• Aggressive lymphomas exhibit complex epigenome and transcriptome alterations driven by EZH2 mutations (EZH2^WT/Mu) and wild-type EZH2 (EZH2^WT/WT).

Purpose of the Study:

• To investigate the interplay between EZH1 and EZH2 in aggressive lymphomas.
• To evaluate the efficacy of EZH1/2 dual inhibitors, specifically valemetostat, as a therapeutic strategy.

Main Methods:

• Epigenome and transcriptome analysis in EZH2^WT/WT and EZH2^WT/Mu lymphoma models.
• Comparative analysis of leading compounds targeting EZH1/2.
• Assessment of synthetic lethality in lymphoma models and primary adult T-cell leukemia-lymphoma (ATL) cells.

Main Results:

• Co-expressed EZH1 and EZH2 exhibit mutual interference and compensatory functions, altering genome-wide distribution and establishing distinct chromatin and gene expression signatures.
• Valemetostat demonstrated potent EZH1/2 dual inhibition with a clear mechanism of action.
• Synthetic lethality was observed across all tested lymphoma models and primary ATL cells.

Conclusions:

• The opposing actions of EZH1/2-polycomb and SWI/SNF complexes are crucial for facultative heterochromatin formation.
• Inactivation of chromatin-associated genes and oncovirus infections can trigger EZH1/2 perturbation and H3K27me3 deposition.
• This study provides a mechanism-based rationale for dual EZH1/2 targeting in cancer epigenome therapy.