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<p>Many epigenetic regulatory factors are targets of the somatic mutations found in patient tumours. Amongst the family of epigenetic regulatory complexes known as Complex of Proteins Associated with Set1 (COMPASS), the enhancer regulators histone-lysine <i>N</i>-methyltransferase 2C (KMT2C)–COMPASS and KMT2D–COMPASS are particularly critical for differentiation and cell fate specification. Their catalytic subunits, including the histone H3 lysine 4 (H3K4) monomethyltransferases KMT2C (also known as MLL3) and KMT2D (also known as MLL4) and the H3K27-specific demethylase lysine-specific demethylase 6A (KDM6A; also known as UTX), are encoded by some of the most frequently mutated genes across human cancers, particularly epithelial cancers. The multifaceted roles of KMT2C–COMPASS and KMT2D–COMPASS, the variety of KMT2C, KMT2D and KDM6A mutations found across all cancer types, and the tissue-specific impacts of compromised enhancer regulatory function have posed challenges for direct therapeutic targeting. However, KMT2C–COMPASS and KMT2D–COMPASS mutations also create tumour-specific and potentially targetable vulnerabilities. In this Review, we discuss the functional roles of KMT2C–COMPASS and KMT2D–COMPASS and the impact of their mutations on cancer progression. We outline potential therapeutic strategies to exploit vulnerabilities in cancer cells with altered KMT2C–COMPASS or KMT2D–COMPASS activity, including aberrant epigenetic regulatory complex activity, metabolic rewiring, defects in cell-cycle control and DNA repair, and increased immunogenicity.</p>

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Enhancer and metabolic rewiring by KMT2C–COMPASS or KMT2D–COMPASS family loss in cancer creates druggable vulnerabilities

  • 期刊论文

  • 发表日期：

    2026年4月24日

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  • Zibo Zhao,
  • Ali Shilatifard

摘要

Many epigenetic regulatory factors are targets of the somatic mutations found in patient tumours. Amongst the family of epigenetic regulatory complexes known as Complex of Proteins Associated with Set1 (COMPASS), the enhancer regulators histone-lysine N-methyltransferase 2C (KMT2C)–COMPASS and KMT2D–COMPASS are particularly critical for differentiation and cell fate specification. Their catalytic subunits, including the histone H3 lysine 4 (H3K4) monomethyltransferases KMT2C (also known as MLL3) and KMT2D (also known as MLL4) and the H3K27-specific demethylase lysine-specific demethylase 6A (KDM6A; also known as UTX), are encoded by some of the most frequently mutated genes across human cancers, particularly epithelial cancers. The multifaceted roles of KMT2C–COMPASS and KMT2D–COMPASS, the variety of KMT2C, KMT2D and KDM6A mutations found across all cancer types, and the tissue-specific impacts of compromised enhancer regulatory function have posed challenges for direct therapeutic targeting. However, KMT2C–COMPASS and KMT2D–COMPASS mutations also create tumour-specific and potentially targetable vulnerabilities. In this Review, we discuss the functional roles of KMT2C–COMPASS and KMT2D–COMPASS and the impact of their mutations on cancer progression. We outline potential therapeutic strategies to exploit vulnerabilities in cancer cells with altered KMT2C–COMPASS or KMT2D–COMPASS activity, including aberrant epigenetic regulatory complex activity, metabolic rewiring, defects in cell-cycle control and DNA repair, and increased immunogenicity.