Open AccessAKT1 E17K ‐Interacting lncRNA SVIL‐AS1 Promotes AKT1 Oncogenic Functions by Preferentially Blocking AKT1 E17K Dephosphorylation
Author(s) -
Wang Jingyi,
Chen Wenying,
Li Qianying,
Yang Ruiyi,
Lin Xiaorong,
Han Ping,
Huang Xiaoming,
Hu Hai,
Luo ManLi
Publication year - 2025
Publication title -
advanced science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.388
H-Index - 100
ISSN - 2198-3844
DOI - 10.1002/advs.202500919
Subject(s) - akt1 , dephosphorylation , phosphorylation , protein kinase b , allosteric regulation , pi3k/akt/mtor pathway , biology , gene knockdown , microbiology and biotechnology , mutant , chemistry , cancer research , signal transduction , phosphatase , biochemistry , receptor , gene
Abstract AKT1 E17K is a gain‐of‐function mutation that constitutively activates the PI3K‐AKT pathway. However, how AKT1 E17K is regulated in cancer pathogenesis remains elusive. Here, RNA immunoprecipitation sequencing (RIP‐seq) is performed to interrogate the AKT1 E17K ‐interacting lncRNAs and identify that SVIL‐AS1 preferentially binds to AKT1 E17K rather than AKT1 WT proteins. It is found that SVIL‐AS1 enhances AKT1 phosphorylation and downstream signaling. SVIL‐AS1 knockdown dramatically inhibits the growth of AKT1 E17K cells in vitro and in vivo. Notably, AKT1 and SVIL‐AS1 interaction is AKT1 phosphorylation‐dependent. SVIL‐AS1 also interacts with PPP2R2A, a subunit of phosphatase PP2A holoenzyme, and blocks the binding of PPP2R2A to AKT1 E17K to prevent AKT1 dephosphorylation. Moreover, AKT1 E17K cells are not effectively inhibited by the allosteric AKT inhibitor, whereas silencing SVIL‐AS1 sensitizes AKT1 E17K cells to AKT1 allosteric inhibitor, as well as the PI3Kα inhibitor. In breast cancer tissues, SVIL‐AS1 is highly expressed and associated with p‐AKT1 level and poor prognosis of patients. Together, the findings discover a novel lncRNA regulator of mutant oncoprotein which preferentially prevents AKT1 E17K dephosphorylation. Targeting SVIL‐AS1 may help to improve the responses to inhibitors of the PI3K‐AKT pathway, especially in AKT1 E17K mutant tumors.