LncRNA AK023948 is a positive regulator of AKT.
LncRNA AK023948 is a positive regulator of AKT.
复制标题
DOI：
10.1038/ncomms14422
复制
发表时间：
2017-02-08
影响因子：
16.6
通讯作者：
Mo YY
中科院分区：
文献类型：
--
作者：
Koirala P;Huang J;Ho TT;Wu F;Ding X;Mo YY
尽管人类长链非编码RNA（lncRNA）的报道数量巨大，但对其中大多数的生理功能知之甚少。本研究使用基于CRISPR/Cas9的协同激活介体（SAM）系统来鉴定能够调节AKT活性的潜在lncRNA。在从该筛选鉴定的lncRNA中，我们证明AK 023948是AKT的正调节因子。AK 023948的敲除抑制，而AK 023948的拯救恢复AKT活性。在机制上，AK 023948与DHX 9和p85功能性相互作用。重要的是，AK 023948是DHX 9和p85之间相互作用所必需的，因此p85稳定性和促进AKT活性。最后，AK 023948在乳腺癌中上调;对TCGA数据集的询问表明，乳腺癌中DHX 9的上调与较差的存活率相关。总之，这项研究证明了两个以前未表征的因子AK 023948和DHX 9是AKT通路中的重要参与者，并且它们的上调可能有助于乳腺肿瘤的进展。许多人类长链非编码RNA（lncRNA）的功能仍然不确定。在这里，作者建立了一个基于CRISPR的筛选功能增益，并鉴定了一种lncRNA，它通过与RNA解旋酶DHX 9相互作用而正向调节AKT活性，从而稳定PI 3 K调节亚基p85。
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. The function of many human long non-coding RNAs (lncRNAs) is still undetermined. Here, the authors setup a gain of function CRISPR-based screen and identify a lncRNA that positively regulates AKT activity by interacting with the RNA helicase DHX9 resulting in stabilization of PI3K regulatory subunit p85.