The lncRNA HOTAIRM1 regulates the degradation of PML-RARA oncoprotein and myeloid cell differentiation by enhancing the autophagy pathway.
The lncRNA HOTAIRM1 regulates the degradation of PML-RARA oncoprotein and myeloid cell differentiation by enhancing the autophagy pathway.
复制标题
lncRNA HOTAIRM1通过增强自噬途径调节PML-RARA癌蛋白的降解和骨髓细胞分化
DOI：
10.1038/cdd.2016.111
复制
发表时间：
2017-02
影响因子：
12.4
通讯作者：
Chen YQ
中科院分区：
文献类型：
--
作者：
Chen ZH;Wang WT;Huang W;Fang K;Sun YM;Liu SR;Luo XQ;Chen YQ
越来越多的证据表明，长链非编码RNA（lncRNA）在不同的细胞环境中具有重要意义。然而，在人类造血过程中，只有极少数lncRNA得到了实验验证和功能注释。在这里，我们报告了一个lncRNA，HOTAIRM 1，这是与骨髓分化，并具有关键作用的癌蛋白PML-RARA的降解和骨髓细胞分化，通过调节自噬途径。我们首次发现HOTAIRM 1具有在细胞中以不同水平表达的不同变体，并且HOTAIRM 1的表达模式与急性早幼粒细胞白血病（APL）患者中PML-RARA癌蛋白的表达模式密切相关。我们进一步发现，HOTAIRM 1的下调可以抑制全反式维甲酸（ATRA）诱导的APL细胞PML-RARA降解，并抑制早幼粒细胞向粒细胞分化的过程。更重要的是，我们发现HOTAIRM 1调节自噬，并且当细胞中HOTAIRM 1表达减少时，自噬体形成受到抑制。最后，通过使用双重荧光素酶活性测定、AGO 2 RNA免疫沉淀和RNA下拉，揭示HOTAIRM 1在包括miR-20 a/106 b、miR-125 b及其靶点ULK 1、E2 F1和DRAM 2的通路中充当microRNA海绵。我们构建了人APL-腹水型SCID小鼠模型，以验证HOTAIRM 1的功能及其体内调控途径。这是首次报道在髓系细胞分化阻断过程中lncRNA调控自噬和PML-RARA癌蛋白降解，提示lncRNA可能是白血病潜在的治疗靶点。
Increasing evidence has indicated that long noncoding RNAs (lncRNAs) are of great importance in different cell contexts. However, only a very small number of lncRNAs have been experimentally validated and functionally annotated during human hematopoiesis. Here, we report an lncRNA, HOTAIRM1, which is associated with myeloid differentiation and has pivotal roles in the degradation of oncoprotein PML-RARA and in myeloid cell differentiation by regulating autophagy pathways. We first revealed that HOTAIRM1 has different variants that are expressed at different levels in cells and that the expression pattern of HOTAIRM1 is closely related to that of the PML-RARA oncoprotein in acute promyelocytic leukemia (APL) patients. We further revealed that the downregulation of HOTAIRM1 could inhibit all-trans retinoic acid (ATRA)-induced degradation of PML-RARA in APL cells and repress the process of differentiation from promyelocytic to granulocytic cells. More importantly, we found that HOTAIRM1 regulates autophagy and that autophagosome formation was inhibited when HOTAIRM1 expression was reduced in the cells. Finally, through the use of a dual luciferase activity assay, AGO2 RNA immunoprecipitation and RNA pull-down, HOTAIRM1 was revealed to act as a microRNA sponge in a pathway that included miR-20a/106b, miR-125b and their targets ULK1, E2F1 and DRAM2. We constructed a human APL-ascites SCID mouse model to validate the function of HOTAIRM1 and its regulatory pathway in vivo. This is the first report showing that a lncRNAs regulates autophagy and the degradation of the PML-RARA oncoprotein during the process of myeloid cell differentiation blockade, suggesting that lncRNAs may be the potential therapeutic targets for leukemia.