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

被引：454

作者：

Lin, Aifu ^{[1
]}

Li, Chunlai ^{[1
]}

Xing, Zhen ^{[1
]}

Hu, Qingsong ^{[1
]}

Liang, Ke ^{[1
]}

Han, Leng ^{[2
]}

Wang, Cheng ^{[3
,4
]}

Hawke, David H. ^{[5
]}

Wang, Shouyu ^{[1
]}

Zhang, Yanyan ^{[1
]}

Wei, Yongkun ^{[1
]}

Ma, Guolin ^{[6
]}

Park, Peter K. ^{[1
]}

Zhou, Jianwei ^{[7
]}

Zhou, Yan ^{[8
]}

Hu, Zhibin ^{[3
,4
]}

Zhou, Yubin ^{[6
]}

Marks, Jeffery R. ^{[9
]}

Liang, Han ^{[5
,10
]}

Hung, Mien-Chie ^{[1
,11
,12
,13
]}

Lin, Chunru ^{[1
,11
]}

Yang, Liuqing ^{[1
,11
,14
]}

机构：

[1] Univ Texas MD Anderson Canc Ctr, Dept Mol & Cellular Oncol, Houston, TX 77030 USA

[2] Univ Texas Hlth Sci Ctr Houston, McGroven Med Sch, Dept Biochem & Mol Biol, Houston, TX 77030 USA

[3] Nanjing Med Univ, Dept Epidemiol & Biostat, Nanjing 210029, Jiangsu, Peoples R China

[4] Nanjing Med Univ, Sch Publ Hlth, Minist Educ MOE, Nanjing 210029, Jiangsu, Peoples R China

[5] Univ Texas MD Anderson Canc Ctr, Dept Syst Biol, Houston, TX 77030 USA

[6] Texas A&M Univ, Hlth Sci Ctr, Inst Biosci & Technol, Ctr Translat Canc Res, Houston, TX 77030 USA

[7] Nanjing Med Univ, Sch Publ Hlth, Dept Mol Cell Biol & Toxicol, 140 Hanzhong Rd, Nanjing 210029, Jiangsu, Peoples R China

[8] Yixing Peoples Hosp, Dept Oncol, 75 Zhenguan Rd, Yixing 214200, Peoples R China

[9] Duke Univ, Sch Med, Div Surg Sci, Dept Surg, Durham, NC 27710 USA

[10] Univ Texas MD Anderson Canc Ctr, Div Quantitat Sci, Dept Bioinformat & Computat Biol, Houston, TX 77030 USA

[11] Univ Texas MD Anderson Canc Ctr, Grad Sch Biomed Sci, Houston, TX 77030 USA

[12] China Med Univ, Ctr Mol Med, Taichung 404, Taiwan

[13] China Med Univ, Grad Inst Canc Biol, Taichung 404, Taiwan

[14] Univ Texas MD Anderson Canc Ctr, Ctr RNA Interference & Noncoding RNAs, Houston, TX 77030 USA

来源：

NATURE CELL BIOLOGY | 2016年 / 18卷 / 02期

关键词：

LONG NONCODING RNAS; TYROSINE KINASE; TUMOR-GROWTH; EPIGENETIC REGULATION; BINDING SITES; HYPOXIA; PROMOTES; PROTEIN; HIF-1; TARGET;

D O I：

10.1038/ncb3295

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

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 HIF1 alpha phosphorylation at Tyr 565 and Ser 797 by BRK and LRRK2, respectively. These events cause HIF1 alpha stabilization, HIF1 alpha-p300 interaction, and activation of HIF1 alpha 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 HIF1 alpha Tyr 565 phosphorylation interferes with Pro 564 hydroxylation, leading to normoxic HIF1 alpha 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.

引用

页码：213 / +

页数：27

共 61 条

[1] Higher Frequency of Certain Cancers in LRRK2 G2019S Mutation Carriers With Parkinson Disease A Pooled Analysis [J].

Agalliu, Ilir ;

San Luciano, Marta ;

Mirelman, Anat ;

Giladi, Nir ;

Waro, Bjorg ;

Aasly, Jan ;

Inzelberg, Rivka ;

Hassin-Baer, Sharon ;

Friedman, Eitan ;

Ruiz-Martinez, Javier ;

Felix Marti-Masso, Jose ;

Orr-Urtreger, Avi ;

Bressman, Susan ;

Saunders-Pullman, Rachel .

JAMA NEUROLOGY, 2015, 72 (01) :58-65

[2] A Micropeptide Encoded by a Putative Long Noncoding RNA Regulates Muscle Performance [J].

Anderson, Douglas M. ;

Anderson, Kelly M. ;

Chang, Chi-Lun ;

Makarewich, Catherine A. ;

Nelson, Benjamin R. ;

McAnally, John R. ;

Kasaragod, Prasad ;

Shelton, John M. ;

Liou, Jen ;

Bassel-Duby, Rhonda ;

Olson, Eric N. .

CELL, 2015, 160 (04) :595-606

[3] Breast Tumor Kinase (Brk/PTK6) Is a Mediator of Hypoxia-Associated Breast Cancer Progression [J].

Anderson, Tarah M. Regan ;

Peacock, Danielle L. ;

Daniel, Andrea R. ;

Hubbard, Gregory K. ;

Lofgren, Kristopher A. ;

Girard, Brian J. ;

Schoerg, Alexandra ;

Hoogewijs, David ;

Wenger, Roland H. ;

Seagroves, Tiffany N. ;

Lange, Carol A. .

CANCER RESEARCH, 2013, 73 (18) :5810-5820

[4] Emerging evidence for functional peptides encoded by short open reading frames [J].

Andrews, Shea J. ;

Rothnagel, Joseph A. .

NATURE REVIEWS GENETICS, 2014, 15 (03) :193-204

[5] Basal-like and triple-negative breast cancers: a critical review with an emphasis on the implications for pathologists and oncologists [J].

Badve, Sunil ;

Dabbs, David J. ;

Schnitt, Stuart J. ;

Baehner, Frederick L. ;

Decker, Thomas ;

Eusebi, Vincenzo ;

Fox, Stephen B. ;

Ichihara, Shu ;

Jacquemier, Jocelyne ;

Lakhani, Sunil R. ;

Palacios, Jose ;

Rakha, Emad A. ;

Richardson, Andrea L. ;

Schmitt, Fernando C. ;

Tan, Puay-Hoon ;

Tse, Gary M. ;

Weigelt, Britta ;

Ellis, Ian O. ;

Reis-Filho, Jorge S. .

MODERN PATHOLOGY, 2011, 24 (02) :157-167

[6] Long Noncoding RNAs: Cellular Address Codes in Development and Disease [J].

Batista, Pedro J. ;

Chang, Howard Y. .

CELL, 2013, 152 (06) :1298-1307

[7] An integrative genomics approach identifies Hypoxia Inducible Factor-1 (HIF-1)-target genes that form the core response to hypoxia [J].

Benita, Yair ;

Kikuchi, Hirotoshi ;

Smith, Andrew D. ;

Zhang, Michael Q. ;

Chung, Daniel C. ;

Xavier, Ramnik J. .

NUCLEIC ACIDS RESEARCH, 2009, 37 (14) :4587-4602

[8] The Soft Agar Colony Formation Assay [J].

Borowicz, Stanley ;

Van Scoyk, Michelle ;

Avasarala, Sreedevi ;

Rathinam, Manoj Kumar Karuppusamy ;

Tauler, Jordi ;

Bikkavilli, Rama Kamesh ;

Winn, Robert A. .

JOVE-JOURNAL OF VISUALIZED EXPERIMENTS, 2014, (92)

[9] Building a better understanding of the intracellular tyrosine kinase FrTK6-BRK by BRK [J].

Brauer, Patrick M. ;

Tyner, Angela L. .

BIOCHIMICA ET BIOPHYSICA ACTA-REVIEWS ON CANCER, 2010, 1806 (01) :66-73

[10] Scan of human genome reveals no new loci under ancient balancing selection [J].

Bubb, K. L. ;

Bovee, D. ;

Buckley, D. ;

Haugen, E. ;

Kibukawa, M. ;

Paddock, M. ;

Palmieri, A. ;

Subramanian, S. ;

Zhou, Y. ;

Kaul, R. ;

Green, P. ;

Olson, M. V. .

GENETICS, 2006, 173 (04) :2165-2177

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