title: The LINK-A lncRNA activates normoxic HIF1α signalling in triple-negative breast cancer.
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.
authors.affiliation: Department of Molecular and Cellular Oncology, The University of Texas M D Anderson Cancer Center, Houston, Texas 77030, USA.
authors.forename: Aifu
authors.initials: A
authors.lastname: Lin
authors.affiliation: Department of Molecular and Cellular Oncology, The University of Texas M D Anderson Cancer Center, Houston, Texas 77030, USA.
authors.forename: Chunlai
authors.initials: C
authors.lastname: Li
authors.affiliation: Department of Molecular and Cellular Oncology, The University of Texas M D Anderson Cancer Center, Houston, Texas 77030, USA.
authors.forename: Zhen
authors.initials: Z
authors.lastname: Xing
authors.affiliation: Department of Molecular and Cellular Oncology, The University of Texas M D Anderson Cancer Center, Houston, Texas 77030, USA.
authors.forename: Qingsong
authors.initials: Q
authors.lastname: Hu
authors.affiliation: Department of Molecular and Cellular Oncology, The University of Texas M D Anderson Cancer Center, Houston, Texas 77030, USA.
authors.forename: Ke
authors.initials: K
authors.lastname: Liang
authors.affiliation: Department of Biochemistry and Molecular Biology, The University of Texas Health Science Center at Houston McGroven Medical School, Houston, Texas 77030, USA.
authors.forename: Leng
authors.initials: L
authors.lastname: Han
authors.affiliation: Department of Epidemiology and Biostatistics and Ministry of Education (MOE), School of Public Health, Nanjing Medical University, 210029, China.
authors.forename: Cheng
authors.initials: C
authors.lastname: Wang
authors.affiliation: Department of System Biology, The University of Texas M D Anderson Cancer Center, Houston, Texas 77030, USA.
authors.forename: David H
authors.identifier: http://orcid.org/0000-0002-6102-7843
authors.initials: DH
authors.lastname: Hawke
authors.affiliation: Department of Molecular and Cellular Oncology, The University of Texas M D Anderson Cancer Center, Houston, Texas 77030, USA.
authors.forename: Shouyu
authors.initials: S
authors.lastname: Wang
authors.affiliation: Department of Molecular and Cellular Oncology, The University of Texas M D Anderson Cancer Center, Houston, Texas 77030, USA.
authors.forename: Yanyan
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Molecular and Cellular Oncology, The University of Texas M D Anderson Cancer Center, Houston, Texas 77030, USA.
authors.forename: Yongkun
authors.initials: Y
authors.lastname: Wei
authors.affiliation: Center for Translational Cancer Research, Institute of Biosciences and Technology, Texas A&M University Health Science Center, Houston, Texas 77030, USA.
authors.forename: Guolin
authors.initials: G
authors.lastname: Ma
authors.affiliation: Department of Molecular and Cellular Oncology, The University of Texas M D Anderson Cancer Center, Houston, Texas 77030, USA.
authors.forename: Peter K
authors.initials: PK
authors.lastname: Park
authors.affiliation: Department of Molecular Cell Biology and Toxicology, School of Public Health, Nanjing Medical University, 140 Hanzhong Road, Nanjing 210029, China.
authors.forename: Jianwei
authors.initials: J
authors.lastname: Zhou
authors.affiliation: Department of Oncology, Yixing People's Hospital, 75 Zhenguan Road, Yixing 214200, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Zhou
authors.affiliation: Department of Epidemiology and Biostatistics and Ministry of Education (MOE), School of Public Health, Nanjing Medical University, 210029, China.
authors.forename: Zhibin
authors.initials: Z
authors.lastname: Hu
authors.affiliation: Center for Translational Cancer Research, Institute of Biosciences and Technology, Texas A&M University Health Science Center, Houston, Texas 77030, USA.
authors.forename: Yubin
authors.initials: Y
authors.lastname: Zhou
authors.affiliation: Department of Surgery, Division of Surgical Science, Duke University, School of Medicine, Durham, North Carolina 27710, USA.
authors.forename: Jeffery R
authors.initials: JR
authors.lastname: Marks
authors.affiliation: Department of System Biology, The University of Texas M D Anderson Cancer Center, Houston, Texas 77030, USA.|Department of Bioinformatics and Computational Biology, Division of Quantitative Sciences, The University of Texas M D Anderson Cancer Center, Houston, Texas 77030, USA.
authors.forename: Han
authors.identifier: http://orcid.org/0000-0001-7633-286X
authors.initials: H
authors.lastname: Liang
authors.affiliation: Department of Molecular and Cellular Oncology, The University of Texas M D Anderson Cancer Center, Houston, Texas 77030, USA.|The Graduate School of Biomedical Sciences, The University of Texas M D Anderson Cancer Center, Houston, Texas 77030, USA.|Center for Molecular Medicine and Graduate Institute of Cancer Biology, China Medical University, Taichung 404, Taiwan.
authors.forename: Mien-Chie
authors.initials: MC
authors.lastname: Hung
authors.affiliation: Department of Molecular and Cellular Oncology, The University of Texas M D Anderson Cancer Center, Houston, Texas 77030, USA.|The Graduate School of Biomedical Sciences, The University of Texas M D Anderson Cancer Center, Houston, Texas 77030, USA.
authors.forename: Chunru
authors.initials: C
authors.lastname: Lin
authors.affiliation: Department of Molecular and Cellular Oncology, The University of Texas M D Anderson Cancer Center, Houston, Texas 77030, USA.|The Graduate School of Biomedical Sciences, The University of Texas M D Anderson Cancer Center, Houston, Texas 77030, USA.|Center for RNA Interference and Non-Coding RNAs, The University of Texas M D Anderson Cancer Center, Houston, Texas 77030, USA.
authors.forename: Liuqing
authors.initials: L
authors.lastname: Yang
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D003593:Cytoplasm / Q000378:metabolism; D050881:E1A-Associated p300 Protein / Q000378:metabolism; D066246:ErbB Receptors / Q000378:metabolism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006019:Glycolysis; D066257:Heparin-binding EGF-like Growth Factor / Q000494:pharmacology; D006801:Humans; D006900:Hydroxylation; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism*; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D008562:Membrane Glycoproteins / Q000378:metabolism; D008819:Mice, Nude; D046912:Multiprotein Complexes; D009363:Neoplasm Proteins / Q000378:metabolism; D010766:Phosphorylation; D011379:Prognosis; D011392:Proline; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D055550:Protein Stability; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D034622:RNA Interference; D062085:RNA, Long Noncoding / Q000235:genetics / Q000378:metabolism*; D012694:Serine; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors; D014158:Transcription, Genetic; D014162:Transfection; D064726:Triple Negative Breast Neoplasms / Q000235:genetics / Q000473:pathology*; D014443:Tyrosine
chemical_list: C503042:GPNMB protein, human; C497442:HIF1A protein, human; D066257:Heparin-binding EGF-like Growth Factor; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; C000608223:LINK-A long non-coding RNA, human; D008562:Membrane Glycoproteins; D046912:Multiprotein Complexes; D009363:Neoplasm Proteins; D062085:RNA, Long Noncoding; D014443:Tyrosine; D012694:Serine; D011392:Proline; D050881:E1A-Associated p300 Protein; C494360:EP300 protein, human; C512478:EGFR protein, human; D066246:ErbB Receptors; D011505:Protein-Tyrosine Kinases; C088375:PTK6 protein, human; C495280:LRRK2 protein, human; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D017346:Protein Serine-Threonine Kinases