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

Aifu Lin; Chunlai Li; Zhen Xing; Qingsong Hu; Ke Liang; Leng Han; Cheng Wang; David H Hawke; Shouyu Wang; Yanyan Zhang; Yongkun Wei; Guolin Ma; Peter K Park; Jianwei Zhou; Yan Zhou; Zhibin Hu; Yubin Zhou; Jeffery R Marks; Han Liang; Mien-Chie Hung; Chunru Lin; Liuqing Yang

doi:10.1038/ncb3295

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.

Authors

Aifu Lin¹, Chunlai Li¹, Zhen Xing¹, Qingsong Hu¹, Ke Liang¹, Leng Han², Cheng Wang³, David H Hawke⁴, Shouyu Wang¹, Yanyan Zhang¹, Yongkun Wei¹, Guolin Ma⁵, Peter K Park¹, Jianwei Zhou⁶, Yan Zhou⁷, Zhibin Hu³, Yubin Zhou⁵, Jeffery R Marks⁸, Han Liang^{4

9}, Mien-Chie Hung^{1

10

11}, Chunru Lin^{1

10}, Liuqing Yang^{1

10

12}

Affiliations

¹ Department of Molecular and Cellular Oncology, The University of Texas M D Anderson Cancer Center, Houston, Texas 77030, USA.
² Department of Biochemistry and Molecular Biology, The University of Texas Health Science Center at Houston McGroven Medical School, Houston, Texas 77030, USA.
³ Department of Epidemiology and Biostatistics and Ministry of Education (MOE), School of Public Health, Nanjing Medical University, 210029, China.
⁴ Department of System Biology, The University of Texas M D Anderson Cancer Center, Houston, Texas 77030, USA.
⁵ Center for Translational Cancer Research, Institute of Biosciences and Technology, Texas A&M University Health Science Center, Houston, Texas 77030, USA.
⁶ Department of Molecular Cell Biology and Toxicology, School of Public Health, Nanjing Medical University, 140 Hanzhong Road, Nanjing 210029, China.
⁷ Department of Oncology, Yixing People's Hospital, 75 Zhenguan Road, Yixing 214200, China.
⁸ Department of Surgery, Division of Surgical Science, Duke University, School of Medicine, Durham, North Carolina 27710, USA.
⁹ Department of Bioinformatics and Computational Biology, Division of Quantitative Sciences, The University of Texas M D Anderson Cancer Center, Houston, Texas 77030, USA.
¹⁰ The Graduate School of Biomedical Sciences, The University of Texas M D Anderson Cancer Center, Houston, Texas 77030, USA.
¹¹ Center for Molecular Medicine and Graduate Institute of Cancer Biology, China Medical University, Taichung 404, Taiwan.
¹² Center for RNA Interference and Non-Coding RNAs, The University of Texas M D Anderson Cancer Center, Houston, Texas 77030, USA.

PMID: 26751287
PMCID: PMC4791069
DOI: 10.1038/ncb3295

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 Serine-Threonine Kinases / metabolism
Protein Stability
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

Abstract

MeSH terms

Substances

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