Kufrin Vida, Seiler Annika, Brilloff Silke, Rothfuß Helen, Küchler Sandra, Schäfer Silvia, Rahimian Elahe, Baumgarten Jonas, Ding Li, Buchholz Frank, Ball Claudia R, Bornhäuser Martin, Glimm Hanno, Bill Marius, Wurm Alexander A
Mildred Scheel Early Career Center, National Center for Tumor Diseases (NCT/UCC) Dresden, Faculty of Medicine and University Hospital Carl Gustav Carus, TUD Dresden University of Technology, Dresden, Germany.
Department of Translational Medical Oncology, National Center for Tumor Diseases (NCT/UCC) Dresden, a partnership between DKFZ, Faculty of Medicine of the TUD Dresden University of Technology, University Hospital Carl Gustav Carus Dresden, and Helmholtz-Zentrum Dresden - Rossendorf (HZDR), Dresden, Germany.
Cell Death Differ. 2025 Mar 27. doi: 10.1038/s41418-025-01479-7.
Lysine acetyltransferase 2 A (KAT2A) plays a pivotal role in epigenetic gene regulation across various types of cancer. In colorectal cancer (CRC), increased KAT2A expression is associated with a more aggressive phenotype. Our study aims to elucidate the molecular underpinnings of KAT2A dependency in CRC and assess the consequences of KAT2A depletion. We 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 of KAT2A dependency. Additionally, we characterized the phenotypic effect of a CRISPR-interference-mediated KAT2A knockdown in CRC cell lines and patient-derived 3D spheroid cultures. Moreover, we assessed the effect of KAT2A depletion within a patient-derived xenograft mouse model in vivo. Our findings reveal that KAT2A dependency is closely associated with microsatellite stability, lower mutational burden, and increased molecular differentiation signatures in CRC, independent of the KAT2A expression levels. KAT2A-dependent CRC cells display higher gene expression levels and enriched H3K27ac marks at gene loci linked to enterocytic differentiation. Furthermore, loss of KAT2A leads to decreased cell growth and viability in vitro and in vivo, downregulation of proliferation- and stem cell-associated genes, and induction of differentiation markers. Altogether, our data show that a specific subset of CRCs with a more differentiated phenotype relies on KAT2A. For these CRC cases, KAT2A might represent a promising novel therapeutic target.
赖氨酸乙酰转移酶2A（KAT2A）在各类癌症的表观遗传基因调控中起着关键作用。在结直肠癌（CRC）中，KAT2A表达增加与更具侵袭性的表型相关。我们的研究旨在阐明CRC中KAT2A依赖性的分子基础，并评估KAT2A缺失的后果。我们通过整合CRISPR - Cas9筛选数据与CRC细胞系中的基因组学、转录组学和整体乙酰化模式进行了全面分析，以确定指示KAT2A依赖性的分子标志物。此外，我们对CRISPR干扰介导的CRC细胞系和患者来源的3D球体培养物中KAT2A敲低的表型效应进行了表征。此外，我们在体内患者来源的异种移植小鼠模型中评估了KAT2A缺失的影响。我们的研究结果表明，KAT2A依赖性与CRC中的微卫星稳定性、较低的突变负担以及增加的分子分化特征密切相关，与KAT2A表达水平无关。KAT2A依赖性CRC细胞在与肠细胞分化相关的基因位点显示出更高的基因表达水平和富集的H3K27ac标记。此外，KAT2A的缺失导致体外和体内细胞生长和活力下降，增殖和干细胞相关基因下调，并诱导分化标志物。总之，我们的数据表明，具有更分化表型的特定CRC亚群依赖于KAT2A。对于这些CRC病例，KAT2A可能是一个有前景的新型治疗靶点。
