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Pan-cancer analysis reveals TAp63-regulated oncogenic lncRNAs that promote cancer progression through AKT activation

Marco Napoli1,2, Xiaobo Li1,2, Hayley D Ackerman1,2

  • 1Department of Molecular Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, 33612, USA.

Nature Communications
|October 15, 2020
PubMed

Insights

Mutations in TP53 and PI3K/AKT pathway activation drive cancer. Researchers identified TROLL-2 and TROLL-3 lncRNAs that activate AKT, promoting cancer by regulating WDR26. These lncRNAs and WDR26 are potential therapeutic targets.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • TP53 mutations and PI3K/AKT pathway activation are common in human cancers.
  • TP53 mutations inhibit the tumor suppressor TAp63.
  • TAp63 plays a role in tumor and metastasis suppression.

Purpose of the Study:

  • To identify TAp63-regulated genes involved in cancer progression.
  • To investigate the role of novel lncRNAs in PI3K/AKT pathway activation.
  • To explore TROLL-2, TROLL-3, and WDR26 as potential therapeutic targets.

Main Methods:

  • Cross-species analysis using mouse models of mammary adenocarcinoma and human breast cancer.
  • Pan-cancer analysis of human cancers and mouse tumor progression models.
  • Investigated the mechanism of lncRNA-mediated AKT activation and WDR26 regulation.

Main Results:

  • Identified two TAp63-regulated oncogenic lncRNAs: TROLL-2 and TROLL-3.
  • Demonstrated that TROLL-2 and TROLL-3 activate AKT signaling, promoting cancer progression.
  • Revealed that these lncRNAs regulate WDR26 nuclear-cytoplasmic translocation via NOLC1.

Conclusions:

  • TROLL-2 and TROLL-3 are key mediators of mutant TP53 and PI3K/AKT pathway-driven cancer.
  • WDR26 is an effector protein regulated by these lncRNAs.
  • TROLL-2, TROLL-3, and WDR26 represent promising therapeutic targets for relevant human tumors.

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