The histone modifier KAT2A presents a selective target in a subset of well-differentiated microsatellite-stable colorectal cancers

Abstract

BackgroundLysine acetyltransferase 2A (KAT2A) plays a pivotal role in epigenetic gene regulation across various types of cancer. In colorectal cancer (CRC), upregulation of KAT2A is associated with a more aggressive phenotype. Our study aims to elucidate the molecular underpinnings ofKAT2Adependency in CRC and assess the consequences ofKAT2Adepletion.MethodsWe conducted a comprehensive analysis by integrating CRISPR-Cas9 screening data with genomics, transcriptomics, and global acetylation patterns in CRC cell lines to pinpoint molecular markers indicative ofKAT2Adependency. Additionally, we characterized the phenotypic effect of a CRISPR-Cas9-mediatedKAT2Aknockout and chemical inhibition of KAT2A in CRC cell lines and patient- derived 3D spheroid cultures.ResultsOur findings reveal thatKAT2Adependency is closely associated with a lower mutational burden and increased differentiation grade in CRC cell lines, independent of theKAT2Aexpression levels.KAT2Adependent CRC cell lines display enriched H3K27ac marks at gene loci linked to enterocytic differentiation. Loss ofKAT2Aleads to decreased cell growth and viability, downregulation of proliferation- and stem cell-associated genes, and induction of differentiation markers.ConclusionA specific subset of CRCs with a more differentiated phenotype relies on KAT2A. For these CRC cases, KAT2A might represent a promising novel therapeutic target.