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

Published

Journal Article

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.

Full Text

Duke Authors

Cited Authors

  • 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; Zhou, Y; Marks, JR; Liang, H; Hung, M-C; Lin, C; Yang, L

Published Date

  • February 2016

Published In

Volume / Issue

  • 18 / 2

Start / End Page

  • 213 - 224

PubMed ID

  • 26751287

Pubmed Central ID

  • 26751287

Electronic International Standard Serial Number (EISSN)

  • 1476-4679

International Standard Serial Number (ISSN)

  • 1465-7392

Digital Object Identifier (DOI)

  • 10.1038/ncb3295

Language

  • eng