Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
Department of Physiology, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
Cancer Res. 2017 Aug 15;77(16):4305-4316. doi: 10.1158/0008-5472.CAN-16-2990. Epub 2017 Jun 26.
Cancer stem-like cells (CSC) evolve to overcome the pressures of reduced oxygen, nutrients or chemically induced cell death, but the mechanisms driving this evolution are incompletely understood. Here, we report that hypoxia-mediated downregulation of the dual specificity phosphatase 2 (DUSP2) is critical for the accumulation of CSC in colorectal cancer. Reduced expression of DUSP2 led to overproduction of COX-2-derived prostaglandin E, which promoted cancer stemness via the EP2/EP4 signaling pathways. Genetic and pharmacological inhibition of PGE biosynthesis or signal transduction ameliorated loss-of-DUSP2-induced tumor growth and cancer stemness. Genome-wide profile analysis revealed that genes regulated by DUSP2 were similar to those controlled by histone deacetylase. Indeed, treatment with novel histone deacetylase inhibitors abolished hypoxia-induced DUSP2 downregulation, COX-2 overexpression, cancer stemness, tumor growth, and drug resistance. Our findings illuminate mechanisms of cancer stemness and suggest new cancer therapy regimens. .
癌症干细胞样细胞 (CSC) 通过进化来克服缺氧、营养物质减少或化学诱导的细胞死亡的压力，但驱动这种进化的机制尚不完全清楚。在这里，我们报告说，低氧介导的双特异性磷酸酶 2 (DUSP2) 的下调对于结直肠癌中 CSC 的积累至关重要。DUSP2 的表达降低导致 COX-2 衍生的前列腺素 E 的过度产生，通过 EP2/EP4 信号通路促进癌症干细胞特性。PGE 生物合成或信号转导的遗传和药理学抑制改善了缺失 DUSP2 诱导的肿瘤生长和癌症干细胞特性。全基因组谱分析表明，受 DUSP2 调控的基因与受组蛋白去乙酰化酶调控的基因相似。事实上，新型组蛋白去乙酰化酶抑制剂的治疗消除了低氧诱导的 DUSP2 下调、COX-2 过表达、癌症干细胞特性、肿瘤生长和耐药性。我们的研究结果阐明了癌症干细胞特性的机制，并提出了新的癌症治疗方案。
