Lysine-specific demethylase 1 promotes the stemness and chemoresistance of Lgr5+ liver cancer initiating cells by suppressing negative regulators of β-catenin signaling
Lysine-specific demethylase 1 promotes the stemness and chemoresistance of Lgr5+ liver cancer initiating cells by suppressing negative regulators of β-catenin signaling
复制标题
赖氨酸特异性去甲基酶1通过抑制β-连环蛋白信号传导的负调节因子促进Lgr5（）肝癌起始细胞的干性和化疗耐药性
DOI：
10.1038/onc.2015.129
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发表时间：
2015-06-11
期刊：
影响因子：
8
通讯作者：
Wang, B.
中科院分区：
文献类型：
--
作者：
Lei, Z-J;Wang, J.;Wang, B.
癌起始细胞（cancer initiating cells，CIC）是恶性肿瘤细胞生长不受限制和产生耐药性的主要原因。组蛋白去甲基化已被证明是干细胞自我更新/分化的关键，但赖氨酸特异性去甲基化酶1（LSD 1）是否调节CIC的干性特性仍然难以捉摸。在这里，我们报告，富含亮氨酸重复的G蛋白偶联受体5（LGR 5）的表达与肝细胞癌（HCC）的进展。Lgr 5（+）HCC细胞的行为与CIC相似，并且具有高度致瘤性和对化疗剂的抗性。重要的是，Lgr 5（+）细胞表达更高水平的LSD 1，从而调节Lgr 5表达并促进Lgr 5（+）CIC的自我更新和耐药性。从机制上讲，LSD 1通过抑制β-连环蛋白信号传导的几种抑制因子（特别是Lgr 5（+）CIC中的Prickle 1和APC）的表达，通过直接调节这些基因启动子处组蛋白H3赖氨酸-4的单甲基化和二甲基化水平，促进β-连环蛋白活化。此外，LSD 1相关的β-连环蛋白信号转导激活对于维持Lgr 5（+）CIC的活性至关重要。总之，我们的研究结果揭示了LSD 1/Prickle 1/APC/β-连环蛋白信号传导轴作为一种新的分子回路调节肝Lgr 5（+）CIC的干性和化疗耐药性，并提供了潜在的靶点，以提高对HCC的化疗疗效。
Cancer initiating cells (CICs) are responsible for the unrestrained cell growth and chemoresistance of malignant tumors. Histone demethylation has been shown to be crucial for self-renewal/differentiation of stem cells, but it remains elusive whether lysine-specific demethylase 1 (LSD1) regulates the stemness properties of CICs. Here we report that the abundant expression of leucinerich repeat-containing G-protein-coupled receptor 5 (Lgr5) is associated with the progression of hepatocellular carcinoma (HCC). Lgr5(+) HCC cells behave similarly to CICs and are highly tumorigenic and resistant to chemotherapeutic agents. Importantly, Lgr5(+) cells express higher levels of LSD1, which in turn regulates Lgr5 expression and promotes the self-renewal and drug resistance of Lgr5(+) CICs. Mechanistically, LSD1 promotes beta-catenin activation by inhibiting the expression of several suppressors of beta-catenin signaling, especially Prickle1 and APC in Lgr5(+) CICs, by directly regulating the levels of mono- and di-methylation of histone H3 lysine-4 at the promoters of these genes. Furthermore, LSD1-associated activation of the beta-catenin signaling is essential for maintaining the activity of Lgr5(+) CICs. Together, our findings unravel the LSD1/Prickle1/APC/beta-catenin signaling axis as a novel molecular circuit regulating the stemness and chemoresistance of hepatic Lgr5(+) CICs and provide potential targets to improve chemotherapeutic efficacies against HCC.