lncRNA directs cooperative epigenetic regulation downstream of chemokine signals

Cell. 2014 Nov 20;159(5):1110-1125. doi: 10.1016/j.cell.2014.10.013. Epub 2014 Nov 13.


lncRNAs are known to regulate a number of different developmental and tumorigenic processes. Here, we report a role for lncRNA BCAR4 in breast cancer metastasis that is mediated by chemokine-induced binding of BCAR4 to two transcription factors with extended regulatory consequences. BCAR4 binding of SNIP1 and PNUTS in response to CCL21 releases the SNIP1's inhibition of p300-dependent histone acetylation, which in turn enables the BCAR4-recruited PNUTS to bind H3K18ac and relieve inhibition of RNA Pol II via activation of the PP1 phosphatase. This mechanism activates a noncanonical Hedgehog/GLI2 transcriptional program that promotes cell migration. BCAR4 expression correlates with advanced breast cancers, and therapeutic delivery of locked nucleic acids (LNAs) targeting BCAR4 strongly suppresses breast cancer metastasis in mouse models. The findings reveal a disease-relevant lncRNA mechanism consisting of both direct coordinated protein recruitment and indirect regulation of transcription factors.

Publication types

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

MeSH terms

  • Animals
  • Breast Neoplasms / metabolism*
  • Cell Line, Tumor
  • DNA-Binding Proteins / metabolism
  • Epigenesis, Genetic
  • Humans
  • Intracellular Signaling Peptides and Proteins / metabolism
  • Kruppel-Like Transcription Factors / genetics
  • Mice
  • Neoplasm Metastasis*
  • Nuclear Proteins / metabolism
  • RNA, Long Noncoding / metabolism*
  • RNA-Binding Proteins / metabolism
  • Signal Transduction
  • Transcriptional Activation
  • Zinc Finger Protein Gli2
  • p300-CBP Transcription Factors / metabolism


  • BCAR4 non-coding RNA, human
  • DNA-Binding Proteins
  • Gli2 protein, mouse
  • Intracellular Signaling Peptides and Proteins
  • Kruppel-Like Transcription Factors
  • Nuclear Proteins
  • PPP1R10 protein, human
  • RNA, Long Noncoding
  • RNA-Binding Proteins
  • SNIP1 protein, human
  • Zinc Finger Protein Gli2
  • p300-CBP Transcription Factors
  • p300-CBP-associated factor

Associated data

  • GEO/GSE60689