title: The LINK-A lncRNA interacts with PtdIns(3,4,5)P3to hyperactivate AKT and confer resistance to AKT inhibitors.
abstract: Phosphatidylinositol-3,4,5-trisphosphate (PtdIns(3,4,5)P3or PIP3) mediates signalling pathways as a second messenger in response to extracellular signals. Although primordial functions of phospholipids and RNAs have been hypothesized in the 'RNA world', physiological RNA-phospholipid interactions and their involvement in essential cellular processes have remained a mystery. We explicate the contribution of lipid-binding long non-coding RNAs (lncRNAs) in cancer cells. Among them, long intergenic non-coding RNA for kinase activation (LINK-A) directly interacts with the AKT pleckstrin homology domain and PIP3at the single-nucleotide level, facilitating AKT-PIP3interaction and consequent enzymatic activation. LINK-A-dependent AKT hyperactivation leads to tumorigenesis and resistance to AKT inhibitors. Genomic deletions of the LINK-A PIP3-binding motif dramatically sensitized breast cancer cells to AKT inhibitors. Furthermore, meta-analysis showed the correlation between LINK-A expression and incidence of a single nucleotide polymorphism (rs12095274: A > G), AKT phosphorylation status, and poor outcomes for breast and lung cancer patients. PIP3-binding lncRNA modulates AKT activation with broad clinical implications.
authors.affiliation: Department of Molecular and Cellular Oncology, The University of Texas MD 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 MD 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 MD 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 MD Anderson Cancer Center, Houston, Texas 77030, USA.
authors.forename: Zhen
authors.initials: Z
authors.lastname: Xing
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 Epidemiology and Biostatistics and Ministry of Education (MOE) Key Lab for Modern Toxicology, School of Public Health, Nanjing Medical University, Nanjing 211166, China.
authors.forename: Cheng
authors.initials: C
authors.lastname: Wang
authors.affiliation: Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.|Department of System Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
authors.forename: Jun
authors.identifier: 0000-0002-1171-7141
authors.initials: J
authors.lastname: Li
authors.affiliation: Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
authors.forename: Yin
authors.initials: Y
authors.lastname: Ye
authors.affiliation: Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
authors.forename: Jun
authors.initials: J
authors.lastname: Yao
authors.affiliation: Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
authors.forename: Ke
authors.initials: K
authors.lastname: Liang
authors.affiliation: Department of Molecular Cell Biology and Toxicology, School of Public Health, Nanjing Medical University, Nanjing 211166, China.
authors.forename: Shouyu
authors.initials: S
authors.lastname: Wang
authors.affiliation: Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
authors.forename: Peter K
authors.initials: PK
authors.lastname: Park
authors.affiliation: Department of Surgery, Division of Surgical Science, Duke University, School of Medicine, Durham, North Carolina 27710, USA.
authors.forename: Jeffrey R
authors.initials: JR
authors.lastname: Marks
authors.affiliation: Department of Oncology, Yixing People's Hospital, Yixing 214200, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Zhou
authors.affiliation: Department of Molecular Cell Biology and Toxicology, School of Public Health, Nanjing Medical University, Nanjing 211166, China.
authors.forename: Jianwei
authors.initials: J
authors.lastname: Zhou
authors.affiliation: Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.|The Graduate School of Biomedical Sciences, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.|Graduate Institute of Cancer Biology and Center for Molecular Medicine, China Medical University, Taichung 404, Taiwan.
authors.forename: Mien-Chie
authors.initials: MC
authors.lastname: Hung
authors.affiliation: Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.|Department of System Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
authors.forename: Han
authors.identifier: 0000-0001-7633-286X
authors.initials: H
authors.lastname: Liang
authors.affiliation: Department of Epidemiology and Biostatistics and Ministry of Education (MOE) Key Lab for Modern Toxicology, School of Public Health, Nanjing Medical University, Nanjing 211166, China.
authors.forename: Zhibin
authors.initials: Z
authors.lastname: Hu
authors.affiliation: Department of Epidemiology and Biostatistics and Ministry of Education (MOE) Key Lab for Modern Toxicology, School of Public Health, Nanjing Medical University, Nanjing 211166, China.
authors.forename: Hongbing
authors.initials: H
authors.lastname: Shen
authors.affiliation: Department of System Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
authors.forename: David H
authors.identifier: 0000-0002-6102-7843
authors.initials: DH
authors.lastname: Hawke
authors.affiliation: Department of Biochemistry and Molecular Biology, The University of Texas Health Science Center at Houston McGovern Medical School, Houston, Texas 77030, USA.
authors.forename: Leng
authors.initials: L
authors.lastname: Han
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.identifier: 0000-0001-7962-0517
authors.initials: Y
authors.lastname: Zhou
authors.affiliation: Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.|The Graduate School of Biomedical Sciences, The University of Texas MD 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 MD Anderson Cancer Center, Houston, Texas 77030, USA.|The Graduate School of Biomedical Sciences, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.|Center for RNA Interference and Non-Coding RNAs, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
authors.forename: Liuqing
authors.initials: L
authors.lastname: Yang
mesh_terms: D001667:Binding, Competitive / Q000187:drug effects; D045744:Cell Line, Tumor; D056915:DNA Copy Number Variations / Q000235:genetics; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D004789:Enzyme Activation / Q000187:drug effects; D005260:Female; D006801:Humans; D008055:Lipids / Q000737:chemistry; D009154:Mutation / Q000235:genetics; D009690:Nucleic Acid Conformation; D018129:Phosphatidylinositol Phosphates / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D062085:RNA, Long Noncoding / Q000737:chemistry / Q000378:metabolism*; D012307:Risk Factors; D064726:Triple Negative Breast Neoplasms / Q000473:pathology
chemical_list: C000608223:LINK-A long non-coding RNA, human; D008055:Lipids; D018129:Phosphatidylinositol Phosphates; D047428:Protein Kinase Inhibitors; D062085:RNA, Long Noncoding; C060974:phosphatidylinositol 3,4,5-triphosphate; D051057:Proto-Oncogene Proteins c-akt