title: Lin28/let-7 axis regulates aerobic glycolysis and cancer progression via PDK1.
abstract: Aberrant expression of Lin28 and let-7 has been observed in many human malignancies. However, its functions and underlying mechanisms remain largely elusive. Here we show that aberrant expression of Lin28 and let-7 facilitates aerobic glycolysis, or Warburg effect, in cancer cells. Mechanistically, we discover that Lin28A and Lin28B enhance, whereas let-7 suppresses, aerobic glycolysis via targeting pyruvate dehydrogenase kinase 1, or PDK1, in a hypoxia- or hypoxia-inducible factor-1 (HIF-1)-independent manner, illustrating a novel pathway to mediate aerobic glycolysis of cancer cells even in ambient oxygen levels. Importantly, we further demonstrate that PDK1 is critical for Lin28A- and Lin28B-mediated cancer proliferation both in vitro and in vivo, establishing a previously unappreciated mechanism by which Lin28/let-7 axis facilitates Warburg effect to promote cancer progression. Our findings suggest a potential rationale to target PDK1 for cancer therapy in malignancies with aberrant expression of Lin28 and let-7.
authors.affiliation: Institute for Cancer Research and CAS Key Laboratory of Innate Immunity and Chronic Disease, Innovation Center for Cell Biology, School of Life Science, University of Science and Technology of China, Hefei 230027, China.
authors.forename: Xiaoyu
authors.initials: X
authors.lastname: Ma
authors.affiliation: Institute for Cancer Research and CAS Key Laboratory of Innate Immunity and Chronic Disease, Innovation Center for Cell Biology, School of Life Science, University of Science and Technology of China, Hefei 230027, China.
authors.forename: Chenchen
authors.initials: C
authors.lastname: Li
authors.affiliation: Institute for Cancer Research and CAS Key Laboratory of Innate Immunity and Chronic Disease, Innovation Center for Cell Biology, School of Life Science, University of Science and Technology of China, Hefei 230027, China.
authors.forename: Linchong
authors.initials: L
authors.lastname: Sun
authors.affiliation: Institute for Cancer Research and CAS Key Laboratory of Innate Immunity and Chronic Disease, Innovation Center for Cell Biology, School of Life Science, University of Science and Technology of China, Hefei 230027, China.
authors.forename: De
authors.initials: D
authors.lastname: Huang
authors.affiliation: Institute for Cancer Research and CAS Key Laboratory of Innate Immunity and Chronic Disease, Innovation Center for Cell Biology, School of Life Science, University of Science and Technology of China, Hefei 230027, China.
authors.forename: Tingting
authors.initials: T
authors.lastname: Li
authors.affiliation: Institute for Cancer Research and CAS Key Laboratory of Innate Immunity and Chronic Disease, Innovation Center for Cell Biology, School of Life Science, University of Science and Technology of China, Hefei 230027, China.
authors.forename: Xiaoping
authors.initials: X
authors.lastname: He
authors.affiliation: Institute for Cancer Research and CAS Key Laboratory of Innate Immunity and Chronic Disease, Innovation Center for Cell Biology, School of Life Science, University of Science and Technology of China, Hefei 230027, China.
authors.forename: Gongwei
authors.initials: G
authors.lastname: Wu
authors.affiliation: Institute for Cancer Research and CAS Key Laboratory of Innate Immunity and Chronic Disease, Innovation Center for Cell Biology, School of Life Science, University of Science and Technology of China, Hefei 230027, China.
authors.forename: Zheng
authors.initials: Z
authors.lastname: Yang
authors.affiliation: Institute for Cancer Research and CAS Key Laboratory of Innate Immunity and Chronic Disease, Innovation Center for Cell Biology, School of Life Science, University of Science and Technology of China, Hefei 230027, China.
authors.forename: Xiuying
authors.initials: X
authors.lastname: Zhong
authors.affiliation: State Key Laboratory of Oncology in Southern China and Department of Experimental Research, Sun Yat-sen University Cancer Center, Guangzhou 510060, China.
authors.forename: Libing
authors.initials: L
authors.lastname: Song
authors.affiliation: Institute for Cancer Research and CAS Key Laboratory of Innate Immunity and Chronic Disease, Innovation Center for Cell Biology, School of Life Science, University of Science and Technology of China, Hefei 230027, China.
authors.forename: Ping
authors.initials: P
authors.lastname: Gao
authors.affiliation: Institute for Cancer Research and CAS Key Laboratory of Innate Immunity and Chronic Disease, Innovation Center for Cell Biology, School of Life Science, University of Science and Technology of China, Hefei 230027, China.
authors.forename: Huafeng
authors.initials: H
authors.lastname: Zhang
mesh_terms: D045744:Cell Line, Tumor; D018450:Disease Progression; D006019:Glycolysis; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D010100:Oxygen / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; C516326:LIN28B protein, human; D035683:MicroRNAs; C000631429:PDK1 protein, human; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D016601:RNA-Binding Proteins; C487931:mirnlet7 microRNA, human; D017346:Protein Serine-Threonine Kinases; D010100:Oxygen