胰腺癌（PC）是最具侵袭性和威胁生命的恶性肿瘤之一，以对细胞毒性治疗的抗药性闻名。这种抗药性越来越被归因于未分化细胞亚群，即胰腺癌干细胞（PCSCs）。相较于其他肿瘤细胞，PCSCs具有更强的进化适应能力，能够逃避化疗的细胞毒性效应。PCSCs对于肿瘤复发至关重要，因为它们具备"类干细胞"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尚不明确。在这里，我们鉴定到组蛋白甲基转移酶KMT2A作为RNA聚合酶结合的PHF5A-PHF14-HMG20A-RAI1蛋白亚复合物的物理结合伴侣及PCSC特性和功能的表观遗传调节器。使用KMT2A-WDR5抑制剂靶向PCSCs的蛋白亚复合物可减弱其自我更新能力、细胞存活能力和体内致瘤能力。© 2023. Springer Nature Limited.

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.© 2023. Springer Nature Limited.