Targeting SWI/SNF ATPases in H3.3K27M diffuse intrinsic pontine gliomas

Area of Science:

• Oncology
• Epigenetics
• Molecular Biology

Background:

• Diffuse midline gliomas (DMGs) with H3K27M mutations are aggressive pediatric brain cancers.
• These tumors exhibit altered histone modifications, specifically reduced H3K27me3 and increased H3K27ac.
• The SWI/SNF chromatin remodeling complex is implicated in cancer and neurodevelopment.

Purpose of the Study:

• To investigate the role of H3K27M mutations in reprogramming the SWI/SNF complex.
• To explore the therapeutic potential of targeting SWI/SNF components in H3K27M gliomas.

Main Methods:

• Analysis of SWI/SNF subunit protein levels in H3K27M gliomas.
• Utilizing a PROTAC (AU-15330) to degrade SWI/SNF ATPase subunits (SMARCA4, SMARCA2) and PBRM1.
• Assessing cytotoxicity, chromatin accessibility (ATAC-Seq), and gene expression changes upon PROTAC treatment.
• Investigating the role of FOXO1 in H3K27M cells.

Main Results:

• H3K27M gliomas show elevated levels of SMARCA4, SMARCA2, and PBRM1.
• PROTAC AU-15330 demonstrated cytotoxicity specifically in H3.3K27M cells.
• AU-15330 reduced chromatin accessibility and global H3K27ac levels.
• Targeting FOXO1 also induced cell death in H3K27M cells.

Conclusions:

• H3K27M mutations up-regulate SMARCA4, impacting SWI/SNF complex activity.
• Combined targeting of SWI/SNF ATPases presents a potential therapeutic strategy for H3K27M-driven pediatric brain tumors.
• FOXO1 is identified as a relevant downstream target in these tumors.