Department of Neonatal Department, Ankang Maternal and Child Health Hospital, Ankang, Shaanxi, 725000, China.
Department of Paediatrics, Affiliated Hospital of JiNing Medical Universrty, Jining, Shandong, 272029, China.
Biochem Biophys Res Commun. 2019 Jan 29;509(1):314-321. doi: 10.1016/j.bbrc.2018.12.133. Epub 2018 Dec 23.
Long non-coding RNAs (lncRNAs) have been identified by accumulating studies as critical regulator in tumorigenesis and tumor development in human cancers, including in acute myeloid leukemia (AML). This study investigated the function and the underlying mechanism of LINC00319 in AML progression. Firstly, the low expression level of LINC00319 in whole blood of healthy individuals was obtained from UCSC, and its upregulation was detected in AML patients as well as AML cell lines. Besides, the prognostic significance of LINC00319 was revealed in AML patients. Functionally, the loss-of-function assays revealed that LINC00319 silence restrained proliferation but stimulated apoptosis in AML cells. Furthermore, LINC00319 expression was demonstrated proportional to MYC level in AML samples and transcriptionally regulated by MYC. Mechanistically, we identified FUS as a shared RNA binding protein (RBP) interacting with both LINC00319 and SIRT6. And LINC00319 regulated SIRT6 expression at post-transcriptional level through FUS-dependent pathway. Last but not least, SIRT6 overexpression rescued the suppressive effect of LINC00319 knockdown on AML cells growth. Overall, our findings unveiled that LINC00319 contributed to AML leukemogenesis via elevating SIRT6 expression, indicating a possible molecular target of LINC00319 for AML treatment.
长链非编码 RNA（lncRNAs）已被多项研究证实为人类癌症（包括急性髓系白血病，AML）发生和发展中的关键调控因子。本研究旨在探讨 LINC00319 在 AML 进展中的作用及其潜在机制。首先，我们从 UCSC 数据库中获得了健康个体全血中 LINC00319 的低表达水平，并发现 AML 患者及 AML 细胞系中 LINC00319 呈上调表达。此外，我们还揭示了 LINC00319 在 AML 患者中的预后意义。功能研究表明，沉默 LINC00319 可抑制 AML 细胞的增殖并促进其凋亡。进一步研究表明，LINC00319 的表达与 AML 样本中 MYC 水平呈正相关，并受 MYC 转录调控。机制研究表明，我们鉴定出 FUS 是与 LINC00319 和 SIRT6 相互作用的共享 RNA 结合蛋白（RBP）。LINC00319 通过 FUS 依赖性途径在转录后水平调节 SIRT6 的表达。最后但同样重要的是，SIRT6 的过表达挽救了 LINC00319 敲低对 AML 细胞生长的抑制作用。总之，我们的研究结果表明，LINC00319 通过上调 SIRT6 表达促进 AML 白血病发生，提示 LINC00319 可能成为 AML 治疗的潜在分子靶点。
