Skip to main content

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

Publication ,  Journal Article
Lin, A; Li, C; Xing, Z; Hu, Q; Liang, K; Han, L; Wang, C; Hawke, DH; Wang, S; Zhang, Y; Wei, Y; Ma, G; Park, PK; Zhou, J; Zhou, Y; Hu, Z ...
Published in: Nat Cell Biol
February 2016

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.

Duke Scholars

Altmetric Attention Stats
Dimensions Citation Stats

Published In

Nat Cell Biol

DOI

EISSN

1476-4679

Publication Date

February 2016

Volume

18

Issue

2

Start / End Page

213 / 224

Location

England

Related Subject Headings

  • Tyrosine
  • Triple Negative Breast Neoplasms
  • Transfection
  • Transcription, Genetic
  • Time Factors
  • Signal Transduction
  • Serine
  • RNA, Long Noncoding
  • RNA Interference
  • Protein-Tyrosine Kinases
 

Citation

APA
Chicago
ICMJE
MLA
NLM
Lin, A., Li, C., Xing, Z., Hu, Q., Liang, K., Han, L., … Yang, L. (2016). The LINK-A lncRNA activates normoxic HIF1α signalling in triple-negative breast cancer. Nat Cell Biol, 18(2), 213–224. https://doi.org/10.1038/ncb3295
Lin, Aifu, Chunlai Li, Zhen Xing, Qingsong Hu, Ke Liang, Leng Han, Cheng Wang, et al. “The LINK-A lncRNA activates normoxic HIF1α signalling in triple-negative breast cancer.Nat Cell Biol 18, no. 2 (February 2016): 213–24. https://doi.org/10.1038/ncb3295.
Lin A, Li C, Xing Z, Hu Q, Liang K, Han L, et al. The LINK-A lncRNA activates normoxic HIF1α signalling in triple-negative breast cancer. Nat Cell Biol. 2016 Feb;18(2):213–24.
Lin, Aifu, et al. “The LINK-A lncRNA activates normoxic HIF1α signalling in triple-negative breast cancer.Nat Cell Biol, vol. 18, no. 2, Feb. 2016, pp. 213–24. Pubmed, doi:10.1038/ncb3295.
Lin A, Li C, Xing Z, Hu Q, Liang K, Han L, Wang C, Hawke DH, Wang S, Zhang Y, Wei Y, Ma G, Park PK, Zhou J, Zhou Y, Hu Z, Marks JR, Liang H, Hung M-C, Lin C, Yang L. The LINK-A lncRNA activates normoxic HIF1α signalling in triple-negative breast cancer. Nat Cell Biol. 2016 Feb;18(2):213–224.

Published In

Nat Cell Biol

DOI

EISSN

1476-4679

Publication Date

February 2016

Volume

18

Issue

2

Start / End Page

213 / 224

Location

England

Related Subject Headings

  • Tyrosine
  • Triple Negative Breast Neoplasms
  • Transfection
  • Transcription, Genetic
  • Time Factors
  • Signal Transduction
  • Serine
  • RNA, Long Noncoding
  • RNA Interference
  • Protein-Tyrosine Kinases