Cancer-associated 2-oxoglutarate analogues modify histone methylation by inhibiting histone lysine demethylases

Area of Science:

• Biochemistry
• Molecular Biology
• Epigenetics

Background:

• Histone lysine demethylases (KDMs) are crucial epigenetic regulators involved in gene expression by modifying chromatin structure.
• Dysregulation of KDMs is frequently observed in various cancers, highlighting their role in tumorigenesis.
• 2-oxoglutarate (2-OG) analogues are implicated in cancer development, particularly in cancers with isocitrate dehydrogenase mutations.

Purpose of the Study:

• To investigate the catalytic and inhibitory properties of human KDM4A, KDM4B, KDM5B, KDM6A, and KDM6B.
• To identify which KDMs are targeted by cancer-associated 2-oxoglutarate (2-OG) analogues.
• To explore the impact of 2-OG analogues on histone methylation in cancer cells.

Main Methods:

• In vitro enzyme activity assays using purified insect cell-produced KDMs and synthetic trimethylated lysine peptides.
• Treatment of breast cancer cell lines with cell-permeable 2-OG analogues.
• Analysis of global histone methylation states in treated cancer cells.

Main Results:

• KDMs exhibit distinct substrate specificities.
• R-2-hydroxyglutarate (R-2HG) effectively inhibited KDM6A, KDM4A, and KDM4B, leading to increased H3K9me3 and H3K27me3 marks in cells.
• KDM5B showed resistance to R-2HG inhibition, while citrate was the most potent inhibitor of KDM6B.

Conclusions:

• KDM enzymatic activity can be inhibited by tumorigenic 2-OG analogues.
• Inhibition of KDMs by accumulating 2-OG analogues may contribute to cancer pathogenesis, especially in cancers with isocitrate dehydrogenase mutations.
• Understanding KDM inhibition by 2-OG analogues offers potential therapeutic strategies for specific cancers.