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

Jingyi Wang1, Wenying Chen2, Qianying Li1

  • 1Department of Otolaryngology-Head and Neck Surgery, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, China.

Advanced Science (Weinheim, Baden-Wurttemberg, Germany)
|March 26, 2025
PubMed

Insights

Researchers discovered a novel long non-coding RNA, SVIL-AS1, that stabilizes the cancer-driving AKT1E17K mutation by preventing its dephosphorylation. Targeting SVIL-AS1 may improve treatments for AKT1E17K-mutant cancers.

Area of Science:

  • Molecular Oncology
  • Cancer Biology
  • RNA Biology

Background:

  • The PI3K-AKT pathway is crucial in cancer, often activated by mutations like AKT1E17K.
  • Understanding the regulation of mutant AKT1 is vital for developing targeted therapies.
  • The role of long non-coding RNAs (lncRNAs) in regulating oncogenic proteins is an emerging area.

Purpose of the Study:

  • To identify lncRNAs that interact with and regulate the AKT1E17K oncoprotein.
  • To elucidate the mechanism by which SVIL-AS1 affects AKT1E17K activity and cancer cell growth.
  • To evaluate the therapeutic potential of targeting SVIL-AS1 in AKT1E17K-mutant cancers.

Main Methods:

  • RNA immunoprecipitation sequencing (RIP-seq) to identify AKT1E17K-interacting lncRNAs.
  • In vitro and in vivo experiments to assess the functional role of SVIL-AS1 in AKT1E17K cells.
  • Co-immunoprecipitation and phosphatase assays to investigate the interaction between SVIL-AS1, AKT1, and PPP2R2A.
  • Analysis of breast cancer patient tissues to correlate SVIL-AS1 expression with clinical outcomes.

Main Results:

  • SVIL-AS1 was identified as a lncRNA that preferentially binds to AKT1E17K over wild-type AKT1.
  • SVIL-AS1 enhances AKT1E17K phosphorylation and downstream signaling, promoting cancer cell growth.
  • SVIL-AS1 inhibits AKT1E17K dephosphorylation by blocking the interaction between AKT1E17K and the phosphatase PPP2R2A.
  • Silencing SVIL-AS1 sensitizes AKT1E17K cells to AKT1 and PI3K inhibitors and is associated with poor prognosis in breast cancer.

Conclusions:

  • SVIL-AS1 acts as a novel lncRNA regulator that stabilizes the AKT1E17K oncoprotein.
  • SVIL-AS1 prevents AKT1E17K dephosphorylation through interaction with PPP2R2A.
  • Targeting SVIL-AS1 offers a potential strategy to enhance the efficacy of PI3K-AKT pathway inhibitors in AKT1E17K-mutant tumors.
Keywords:
AKT1E17K mutationPP2ASVIL‐AS1lncRNA

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