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journal article·2025-05Open access

AKT1E17K‐Interacting lncRNA SVIL‐AS1 Promotes AKT1 Oncogenic Functions by Preferentially Blocking AKT1E17K Dephosphorylation

Jingyi Wang, Wenying Chen, Qianying Li, Ruiyi Yang, Xiaorong Lin, Ping Han, Xiaoming Huang, Hai Hu, Man‐Li Luo

Advanced Science· Volume 12· Issue 19
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Abstract

Abstract AKT1E17K is a gain‐of‐function mutation that constitutively activates the PI3K‐AKT pathway. However, how AKT1E17K is regulated in cancer pathogenesis remains elusive. Here, RNA immunoprecipitation sequencing (RIP‐seq) is performed to interrogate the AKT1E17K‐interacting lncRNAs and identify that SVIL‐AS1 preferentially binds to AKT1E17K rather than AKT1WT proteins. It is found that SVIL‐AS1 enhances AKT1 phosphorylation and downstream signaling. SVIL‐AS1 knockdown dramatically inhibits the growth of AKT1E17K 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 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 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 AKT1E17K dephosphorylation. Targeting SVIL‐AS1 may help to improve the responses to inhibitors of the PI3K‐AKT pathway, especially in AKT1E17K mutant tumors.
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Research context

OpenAlex topics: Cancer-related molecular mechanisms research · RNA modifications and cancer · PI3K/AKT/mTOR signaling in cancer

SciVX discovery tags are terminology-based. OpenAlex topics are source-provided classifications.

Affiliations

Department of Otolaryngology‐Head and Neck Surgery Sun Yat‐Sen Memorial Hospital Sun Yat‐Sen University Guangzhou 510120 China

Department of Gastroenterology Sun Yat‐Sen Memorial Hospital Sun Yat‐Sen University Guangzhou 510120 China

Department of Oncology Sun Yat‐Sen Memorial Hospital Sun Yat‐sen University Guangzhou 510120 China

Diagnosis and Treatment Center of Breast Diseases Shantou Central Hospital Shantou 515031 China

Breast Cancer Center Zhejiang Cancer Hospital Hangzhou Institute of Medicine Chinese Academy of Sciences Hangzhou 310022 China

Medical Research Center Sun Yat‐Sen Memorial Hospital Sun Yat‐Sen University Guangzhou 510120 China

Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation Guangdong‐Hong Kong Joint Laboratory for RNA Medicine Sun Yat‐Sen Memorial Hospital Sun Yat‐Sen University Guangzhou 510120 China

Funding

National Key Research and Development Program of China · National Natural Science Foundation of China · China Postdoctoral Science Foundation · Guangdong Provincial Department of Science and Technology

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