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

Nat Commun. 2020 Oct 14;11(1):5156. doi: 10.1038/s41467-020-18973-w.


The most frequent genetic alterations across multiple human cancers are mutations in TP53 and the activation of the PI3K/AKT pathway, two events crucial for cancer progression. Mutations in TP53 lead to the inhibition of the tumour and metastasis suppressor TAp63, a p53 family member. By performing a mouse-human cross species analysis between the TAp63 metastatic mammary adenocarcinoma mouse model and models of human breast cancer progression, we identified two TAp63-regulated oncogenic lncRNAs, TROLL-2 and TROLL-3. Further, using a pan-cancer analysis of human cancers and multiple mouse models of tumour progression, we revealed that these two lncRNAs induce the activation of AKT to promote cancer progression by regulating the nuclear to cytoplasmic translocation of their effector, WDR26, via the shuttling protein NOLC1. Our data provide preclinical rationale for the implementation of these lncRNAs and WDR26 as therapeutic targets for the treatment of human tumours dependent upon mutant TP53 and/or the PI3K/AKT pathway.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Adaptor Proteins, Signal Transducing / genetics
  • Adaptor Proteins, Signal Transducing / metabolism
  • Adenocarcinoma / genetics*
  • Adenocarcinoma / pathology
  • Animals
  • Breast Neoplasms / genetics*
  • Breast Neoplasms / pathology
  • Cell Line, Tumor
  • Disease Progression
  • Female
  • Gene Expression Regulation, Neoplastic*
  • Humans
  • Mammary Glands, Animal / cytology
  • Mammary Neoplasms, Experimental / genetics*
  • Mammary Neoplasms, Experimental / pathology
  • Mice
  • Nuclear Proteins / metabolism
  • Phosphoproteins / metabolism
  • Primary Cell Culture
  • Proto-Oncogene Proteins c-akt / metabolism
  • RNA, Long Noncoding / metabolism*
  • RNA-Seq
  • Signal Transduction / genetics
  • Tissue Array Analysis
  • Trans-Activators / genetics
  • Trans-Activators / metabolism*
  • Transcription Factors / genetics
  • Transcription Factors / metabolism*
  • Tumor Suppressor Protein p53 / genetics
  • Tumor Suppressor Proteins / genetics
  • Tumor Suppressor Proteins / metabolism*
  • Xenograft Model Antitumor Assays


  • Adaptor Proteins, Signal Transducing
  • NOLC1 protein, human
  • Nolc1 protein, mouse
  • Nuclear Proteins
  • Phosphoproteins
  • RNA, Long Noncoding
  • TP53 protein, human
  • TP63 protein, human
  • Trans-Activators
  • Transcription Factors
  • Trp53 protein, mouse
  • Trp63 protein, mouse
  • Tumor Suppressor Protein p53
  • Tumor Suppressor Proteins
  • WDR26 protein, human
  • WDR26 protein, mouse
  • Proto-Oncogene Proteins c-akt