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AKT1E17K-interacting lncRNA SVIL-AS1 promotes AKT1 oncogenic functions by sustaining its phosphorylation

ABSTRACT: AKT1 E17K, occurring at low frequency in a broad range of cancer types, is a gain-of-function mutation that constitutively activates the PI3K-AKT pathway. However, how AKT1E17K is regulated in cancer pathogenesis remains elusive. Here, we interrogate the AKT1E17K-interacting lncRNAs and identify that SVIL-AS1 preferentially binds to AKT1E17K rather than AKT1WT proteins. We find that SVIL-AS1 enhances AKT1 phosphorylation and downstream signaling. SVIL-AS1 knockdown dramatically inhibits the growth of AKT1E17K cells in intro 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 AKT1E17K to prevent AKT1 dephosphorylation. Moreover, AKT1E17K cells are not effectively inhibited by the allosteric AKT inhibitor, whereas silencing SVIL-AS1 sensitizes AKT1E17K cells to AKT1 allosteric inhibitor, as well as the PI3K inhibitor. In breast cancer tissues, SVIL-AS1 is highly expressed and associated with p-AKT1 level and poor prognosis of patients. Together, our findings highlight a previously unappreciated role of lncRNA SVIL-AS1 in regulating AKT1 dephosphorylation, which serves as a promising therapeutic target for AKT1E17K tumors.

ORGANISM(S): Homo sapiens

PROVIDER: GSE268685 | GEO | 2025/05/30

REPOSITORIES: GEO

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Project description:Hyperactivation of the PI3K/AKT pathway is observed in most NSCLCs, promoting proliferation, migration and resistance to therapy. AKT can be activated through several mechanisms that include loss of the negative regulator PTEN, activating mutations of the catalytic subunit of the positive regulator phosphatydil-inositol-3â phosphate kinase (PIK3CA) and/or mutations of AKT1 itself. However, whereas the effects of AKT activation on mRNAs and proteins in the cell are fairly clear, the role of miRNAs as downstream targets of activated PI3K/AKT signalling is still poorly defined so far. To identify miRNAs that are targets of constitutive signalling of PI3K/AKT in lung cancer cells, we performed miRNA profiling of human lung epithelial cells expressing active mutant AKT1 (E17K), active mutant PI3KCA (E545K) or that are silenced for PTEN. We identified 28 differentially expressed miRNAs (8 up-regulated, 20 down-regulated) that were common to BEAS-AKT1-E17K, BEAS-PIK3CA-E545K and BEAS-shPTEN cells. Among the 8 up-regulated miRNAs that were common to all the alterations, the miRNA most consistently up-regulated by activation of the PI3K/AKT pathway in BEAS-2B cells was miR-196a. The results reported here demonstrate that miR-196a acts as oncogene downstream the PI3K/AKT pathway, mediating the proliferative, pro-migratory and tumorigenic activity of this pathway in NSCLC cells by targeting FoxO1 and p27 expression. By adoptive expression of miR-196a in BEAS-2B cells, we demonstrated that miR-196a stimulates anchorage-dependent and -independent proliferation, migration and tumorigenicity in BEAS-2B cells. On the other hand, by use of antimir-196a in NCI-H460 cells to silence the endogenous expression of miR-196a, we demonstrate that miR-196a plays a pivotal role in mediating the stimulation of proliferation, migration and tumorigenicity induced by aberrant activation of PI3K/AKT signalling. Accordingly, we found that miR-196a was significantly overexpressed in human NSCLC-derived cell lines (n=6) and primary lung cancer samples (n=28). Finally, based on predicted binding sites for miR-196a by microRNA analysis software, we found that miR-196a affects protein levels of FoxO1 and p27 in NSCLC cells.

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AKT1E17K-interacting lncRNA SVIL-AS1 promotes AKT1 oncogenic functions by sustaining its phosphorylation

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