KLF5 regulated lncRNA RP1 promotes the growth and metastasis of breast cancer via repressing p27kip1 translation
KLF5 regulated lncRNA RP1 promotes the growth and metastasis of breast cancer via repressing p27kip1 translation
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KLF5调节的lncRNA RP1通过抑制p27kip1翻译促进乳腺癌的生长和转移
DOI：
10.1038/s41419-019-1566-5
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发表时间：
2019-05-09
影响因子：
9
通讯作者：
Zheng, Guopei
中科院分区：
文献类型：
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作者：
Jia, Xiaoting;Shi, Lejuan;Zheng, Guopei
越来越多的证据表明，lncRNA（长链非编码RNA）在人类癌症中发挥重要作用。乳腺癌是一种异质性疾病，并且lncRNA在乳腺癌中的潜在参与仍未被探索。在这项研究中，我们表征了一种新的lncRNA，RP 1 -5O6.5（称为RP 1）。我们发现RP 1在乳腺癌中高表达，并预测乳腺癌患者预后不良。功能获得和功能丧失实验表明RP 1在体内外均能促进乳腺癌细胞的增殖和转移。RP 1通过抑制p27 kip 1蛋白表达维持乳腺癌细胞的EMT和干性状态。RP 1与p-4 E-BP 1/eIF 4 E复合物结合，阻止eIF 4 E与eIF 4G相互作用，从而降低p27 kip 1 mRNA的翻译效率。此外，我们发现p27 kip 1明显下调Snail 1而不是ZEB 1，以抑制乳腺癌细胞的侵袭。乳腺癌组织中Kruppel样因子5（KLF 5）与RP 1呈正相关。此外，我们证明了KLF 5募集p300到RP 1启动子以增强RP 1表达。综上所述，我们的研究结果表明，KLF 5调控的RP 1通过抑制p27 kip 1在乳腺癌中发挥致癌作用，为专注于RP 1的治疗方法的临床研究提供支持。
Increasing evidence suggest that lncRNAs (long noncoding RNAs) play important roles in human cancer. Breast cancer is a heterogeneous disease and the potential involvement of lncRNAs in breast cancer remains unexplored. In this study, we characterized a novel lncRNA, RP1-5O6.5 (termed as RP1). We found that RP1 was highly expressed in breast cancer and predicted poor prognosis of breast cancer patients. Gain-of-function and loss-of-function assays showed that RP1 promoted the proliferation and metastasis of breast cancer cells in vitro and in vivo. Mechanistically, RP1 maintained the EMT and stemness states of breast cancer cells via repressing p27kip1 protein expression. RP1 combined with the complex p-4E-BP1/eIF4E to prevent eIF4E from interacting with eIF4G, therefore attenuating the translational efficiency of p27kip1 mRNA. Furthermore, we found that p27kip1 evidently downregulated Snail1 but not ZEB1 to inhibit invasion of breast cancer cells. Kruppel-like factor 5 (KLF5) was positively correlated with RP1 in breast cancer tissues. Moreover, we demonstrated that KLF5 recruited p300 to the RP1 promoter to enhance RP1 expression. Taken together, our findings demonstrated that KLF5-regulated RP1 plays an oncogenic role in breast cancer by suppressing p27kip1, providing support for the clinical investigation of therapeutic approaches focusing on RP1.