长链非编码 RNA AK023948 是 AKT 的正调控因子。
LncRNA AK023948 is a positive regulator of AKT.
机构信息
Cancer Institute, University of Mississippi Medical Center, Jackson, Mississippi 39216, USA.
Department of Biochemistry, University of Mississippi Medical Center, Jackson, Mississippi 39216, USA.
出版信息
Nat Commun. 2017 Feb 8;8:14422. doi: 10.1038/ncomms14422.
Despite the overwhelming number of human long non-coding RNAs (lncRNAs) reported so far, little is known about their physiological functions for the majority of them. The present study uses a CRISPR/Cas9-based synergistic activation mediator (SAM) system to identify potential lncRNAs capable of regulating AKT activity. Among lncRNAs identified from this screen, we demonstrate that AK023948 is a positive regulator for AKT. Knockout of AK023948 suppresses, whereas rescue with AK023948 restores the AKT activity. Mechanistically, AK023948 functionally interacts with DHX9 and p85. Importantly, AK023948 is required for the interaction between DHX9 and p85 to hence the p85 stability and promote AKT activity. Finally, AK023948 is upregulated in breast cancer; interrogation of TCGA data set indicates that upregulation of DHX9 in breast cancer is associated with poor survival. Together, this study demonstrates two previously uncharacterized factors AK023948 and DHX9 as important players in the AKT pathway, and that their upregulation may contribute to breast tumour progression.
尽管目前已经报道了大量的人类长链非编码 RNA（lncRNA），但对于其中的大多数，它们的生理功能还知之甚少。本研究利用基于 CRISPR/Cas9 的协同激活调节剂（SAM）系统来鉴定潜在的能够调节 AKT 活性的 lncRNA。在这个筛选中鉴定出的 lncRNA 中，我们证明 AK023948 是 AKT 的正调控因子。敲除 AK023948 会抑制 AKT 活性，而用 AK023948 进行挽救则可恢复 AKT 活性。从机制上讲，AK023948 与 DHX9 和 p85 具有功能相互作用。重要的是，AK023948 对于 DHX9 和 p85 之间的相互作用是必需的，从而促进了 p85 的稳定性并增强了 AKT 活性。最后，AK023948 在乳腺癌中上调；对 TCGA 数据集的分析表明，乳腺癌中 DHX9 的上调与不良预后相关。总之，这项研究表明，以前未被表征的两个因子 AK023948 和 DHX9 是 AKT 通路中的重要成员，它们的上调可能有助于乳腺癌的进展。
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