KMT2A 与 PHF5A-PHF14-HMG20A-RAI1 亚复合物在胰腺癌干细胞中相互作用，并通过表观遗传调控其特征。
KMT2A associates with PHF5A-PHF14-HMG20A-RAI1 subcomplex in pancreatic cancer stem cells and epigenetically regulates their characteristics.
机构信息
Botnar Research Centre, Nuffield Department of Orthopaedics, Rheumatology, and Musculoskeletal Sciences, University of Oxford, Oxford, UK.
Institute of Biomedicine and Translational Medicine, Faculty of Medicine, University of Tartu, Tartu, Estonia.
出版信息
Nat Commun. 2023 Sep 14;14(1):5685. doi: 10.1038/s41467-023-41297-4.
Pancreatic cancer (PC), one of the most aggressive and life-threatening human malignancies, is known for its resistance to cytotoxic therapies. This is increasingly ascribed to the subpopulation of undifferentiated cells, known as pancreatic cancer stem cells (PCSCs), which display greater evolutionary fitness than other tumor cells to evade the cytotoxic effects of chemotherapy. PCSCs are crucial for tumor relapse as they possess 'stem cell-like' features that are characterized by self-renewal and differentiation. However, the molecular mechanisms that maintain the unique characteristics of PCSCs are poorly understood. Here, we identify the histone methyltransferase KMT2A as a physical binding partner of an RNA polymerase-associated PHF5A-PHF14-HMG20A-RAI1 protein subcomplex and an epigenetic regulator of PCSC properties and functions. Targeting the protein subcomplex in PCSCs with a KMT2A-WDR5 inhibitor attenuates their self-renewal capacity, cell viability, and in vivo tumorigenicity.
胰腺癌（PC）是最具侵袭性和致命性的人类恶性肿瘤之一，以对细胞毒性疗法的耐药性而闻名。这越来越归因于未分化细胞亚群，即胰腺癌细胞干细胞（PCSCs），它们比其他肿瘤细胞具有更高的进化适应性，能够逃避化疗的细胞毒性作用。PCSCs 是肿瘤复发的关键，因为它们具有“干细胞样”特征，表现为自我更新和分化。然而，维持 PCSCs 独特特征的分子机制还知之甚少。在这里，我们确定组蛋白甲基转移酶 KMT2A 是 RNA 聚合酶相关 PHF5A-PHF14-HMG20A-RAI1 蛋白亚复合物的物理结合伴侣，也是 PCSC 特性和功能的表观遗传调节剂。用 KMT2A-WDR5 抑制剂靶向 PCSCs 中的蛋白质亚复合物会减弱其自我更新能力、细胞活力和体内致瘤性。
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