Department of Anatomical and Cellular Pathology, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong SAR, China.
Institute of Digestive Disease, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Science, The Chinese University of Hong Kong, Hong Kong SAR, China.
Theranostics. 2022 Sep 6;12(15):6509-6526. doi: 10.7150/thno.75431. eCollection 2022.
Hyperactivation of Hippo-Yes-associated protein (YAP) signaling pathway governs tumorigenesis of gastric cancer (GC). Here we reveal that minichromosome maintenance complex component 6 (MCM6) is a critical transcriptional target of YAP in GC. We aim to investigate the function, mechanism of action, and clinical implication of MCM6 in GC. The downstream targets of YAP were screened by RNA sequencing (RNA-seq) and microarray, and further validated by chromatin immunoprecipitation PCR and luciferase reporter assays. The clinical implication of MCM6 was assessed in multiple GC cohorts. Biological function of MCM6 was evaluated , in patient-derived organoids, and . RNA-seq was performed to unravel downstream signaling of MCM6. Potential MCM6 inhibitor was identified and the effect of MCM6 inhibition on GC growth was evaluated. Integrative RNA sequencing and microarray analyses revealed MCM6 as a potential YAP downstream target in GC. The YAP-TEAD complex bound to the promoter of MCM6 to induce its transcription. Increased MCM6 expression was commonly observed in human GC tissues and predicted poor patients survival. MCM6 knockdown suppressed proliferation and migration of GC cells and patient-derived organoids, and attenuated xenograft growth and peritoneal metastasis in mice. Mechanistically, MCM6 activated PI3K/Akt/GSK3β signaling to support YAP-potentiated gastric tumorigenicity and metastasis. Furthermore, MCM6 deficiency sensitized GC cells to chemo- or radiotherapy by causing DNA breaks and blocking ATR/Chk1-mediated DNA damage response (DDR), leading to exacerbated cell death and tumor regression. As there are no available MCM6 inhibitors, we performed high-throughput virtual screening and identified purpureaside C as a novel MCM6 inhibitor. Purpureaside C not only suppressed GC growth but also synergized with 5-fluorouracil to induce cell death. Hyperactivated YAP in GC induces MCM6 transcription via binding to its promoter. YAP-MCM6 axis facilitates GC progression by inducing PI3K/Akt signaling. Targeting MCM6 suppresses GC growth and sensitizes GC cells to genotoxic agents by modulating ATR/Chk1-dependent DDR, providing a promising strategy for GC treatment.
Hippo-Yes 相关蛋白 (YAP) 信号通路的过度激活控制着胃癌 (GC) 的肿瘤发生。在这里，我们揭示了微小染色体维持复合物成分 6 (MCM6) 是 GC 中 YAP 的关键转录靶标。我们旨在研究 MCM6 在 GC 中的功能、作用机制和临床意义。通过 RNA 测序 (RNA-seq) 和微阵列筛选 YAP 的下游靶标，并通过染色质免疫沉淀 PCR 和荧光素酶报告基因测定进一步验证。在多个 GC 队列中评估了 MCM6 的临床意义。在患者来源的类器官和体内评估了 MCM6 的生物学功能。进行 RNA-seq 以揭示 MCM6 的下游信号。鉴定了潜在的 MCM6 抑制剂，并评估了 MCM6 抑制对 GC 生长的影响。综合 RNA 测序和微阵列分析显示 MCM6 是 GC 中潜在的 YAP 下游靶标。YAP-TEAD 复合物结合到 MCM6 的启动子上诱导其转录。在人类 GC 组织中普遍观察到 MCM6 表达增加，并预测患者预后不良。MCM6 敲低抑制 GC 细胞和患者来源的类器官的增殖和迁移，并减弱小鼠异种移植的生长和腹膜转移。在机制上，MCM6 激活 PI3K/Akt/GSK3β 信号以支持 YAP 增强的胃肿瘤发生和转移。此外，MCM6 缺乏通过引起 DNA 断裂和阻断 ATR/Chk1 介导的 DNA 损伤反应 (DDR) 使 GC 细胞对化疗或放疗敏感，导致细胞死亡加剧和肿瘤消退。由于没有可用的 MCM6 抑制剂，我们进行了高通量虚拟筛选，并鉴定出紫菀酰胺 C 为一种新型 MCM6 抑制剂。紫菀酰胺 C 不仅抑制 GC 生长，而且与 5-氟尿嘧啶协同诱导细胞死亡。GC 中的过度激活 YAP 通过结合其启动子诱导 MCM6 转录。YAP-MCM6 轴通过诱导 PI3K/Akt 信号促进 GC 进展。靶向 MCM6 通过调节 ATR/Chk1 依赖性 DDR 抑制 GC 生长并使 GC 细胞对遗传毒性药物敏感，为 GC 治疗提供了一种有前途的策略。
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