The LINK-A lncRNA activates normoxic HIF1α signalling in triple-negative breast cancer

Nat Cell Biol. 2016 Feb;18(2):213-24. doi: 10.1038/ncb3295. Epub 2016 Jan 11.

Abstract

Although long non-coding RNAs (lncRNAs) predominately reside in the nucleus and exert their functions in many biological processes, their potential involvement in cytoplasmic signal transduction remains unexplored. Here, we identify a cytoplasmic lncRNA, LINK-A (long intergenic non-coding RNA for kinase activation), which mediates HB-EGF-triggered, EGFR:GPNMB heterodimer-dependent HIF1α phosphorylation at Tyr 565 and Ser 797 by BRK and LRRK2, respectively. These events cause HIF1α stabilization, HIF1α-p300 interaction, and activation of HIF1α transcriptional programs under normoxic conditions. Mechanistically, LINK-A facilitates the recruitment of BRK to the EGFR:GPNMB complex and BRK kinase activation. The BRK-dependent HIF1α Tyr 565 phosphorylation interferes with Pro 564 hydroxylation, leading to normoxic HIF1α stabilization. Both LINK-A expression and LINK-A-dependent signalling pathway activation correlate with triple-negative breast cancer (TNBC), promoting breast cancer glycolysis reprogramming and tumorigenesis. Our findings illustrate the magnitude and diversity of cytoplasmic lncRNAs in signal transduction and highlight the important roles of lncRNAs in cancer.

MeSH terms

  • Animals
  • Cell Line, Tumor
  • Cytoplasm / metabolism
  • E1A-Associated p300 Protein / metabolism
  • ErbB Receptors / metabolism
  • Female
  • Gene Expression Regulation, Neoplastic
  • Glycolysis
  • Heparin-binding EGF-like Growth Factor / pharmacology
  • Humans
  • Hydroxylation
  • Hypoxia-Inducible Factor 1, alpha Subunit / genetics
  • Hypoxia-Inducible Factor 1, alpha Subunit / metabolism*
  • Leucine-Rich Repeat Serine-Threonine Protein Kinase-2
  • Membrane Glycoproteins / metabolism
  • Mice, Nude
  • Multiprotein Complexes
  • Neoplasm Proteins / metabolism
  • Phosphorylation
  • Prognosis
  • Proline
  • Protein Stability
  • Protein-Serine-Threonine Kinases / metabolism
  • Protein-Tyrosine Kinases / metabolism
  • RNA Interference
  • RNA, Long Noncoding / genetics
  • RNA, Long Noncoding / metabolism*
  • Serine
  • Signal Transduction* / drug effects
  • Time Factors
  • Transcription, Genetic
  • Transfection
  • Triple Negative Breast Neoplasms / genetics
  • Triple Negative Breast Neoplasms / pathology*
  • Tyrosine

Substances

  • GPNMB protein, human
  • HIF1A protein, human
  • Heparin-binding EGF-like Growth Factor
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • LINK-A long non-coding RNA, human
  • Membrane Glycoproteins
  • Multiprotein Complexes
  • Neoplasm Proteins
  • RNA, Long Noncoding
  • Tyrosine
  • Serine
  • Proline
  • E1A-Associated p300 Protein
  • EP300 protein, human
  • EGFR protein, human
  • ErbB Receptors
  • Protein-Tyrosine Kinases
  • PTK6 protein, human
  • LRRK2 protein, human
  • Leucine-Rich Repeat Serine-Threonine Protein Kinase-2
  • Protein-Serine-Threonine Kinases