title: Aerobic glycolysis tunes YAP/TAZ transcriptional activity.
abstract: Increased glucose metabolism and reprogramming toward aerobic glycolysis are a hallmark of cancer cells, meeting their metabolic needs for sustained cell proliferation. Metabolic reprogramming is usually considered as a downstream consequence of tumor development and oncogene activation; growing evidence indicates, however, that metabolism on its turn can support oncogenic signaling to foster tumor malignancy. Here, we explored how glucose metabolism regulates gene transcription and found an unexpected link with YAP/TAZ, key transcription factors regulating organ growth, tumor cell proliferation and aggressiveness. When cells actively incorporate glucose and route it through glycolysis, YAP/TAZ are fully active; when glucose metabolism is blocked, or glycolysis is reduced, YAP/TAZ transcriptional activity is decreased. Accordingly, glycolysis is required to sustain YAP/TAZ pro-tumorigenic functions, and YAP/TAZ are required for the full deployment of glucose growth-promoting activity. Mechanistically we found that phosphofructokinase (PFK1), the enzyme regulating the first committed step of glycolysis, binds the YAP/TAZ transcriptional cofactors TEADs and promotes their functional and biochemical cooperation with YAP/TAZ. Strikingly, this regulation is conserved in Drosophila, where phosphofructokinase is required for tissue overgrowth promoted by Yki, the fly homologue of YAP. Moreover, gene expression regulated by glucose metabolism in breast cancer cells is strongly associated in a large dataset of primary human mammary tumors with YAP/TAZ activation and with the progression toward more advanced and malignant stages. These findings suggest that aerobic glycolysis endows cancer cells with particular metabolic properties and at the same time sustains transcription factors with potent pro-tumorigenic activities such as YAP/TAZ.
authors: Department of Molecular Medicine, University of Padova, Padua, Italy.
authors: Elena
authors: E
authors: Enzo
authors: Department of Molecular Medicine, University of Padova, Padua, Italy.
authors: Giulia
authors: G
authors: Santinon
authors: Department of Molecular Medicine, University of Padova, Padua, Italy.
authors: Arianna
authors: A
authors: Pocaterra
authors: Department of Molecular Medicine, University of Padova, Padua, Italy.
authors: Mariaceleste
authors: M
authors: Aragona
authors: Department of Woman and Child Health, University of Padova, Padua, Italy.
authors: Silvia
authors: S
authors: Bresolin
authors: Department of Life Sciences, Center for Genome Research University of Modena and Reggio Emilia, Modena, Italy.
authors: Mattia
authors: M
authors: Forcato
authors: Department of Pharmacy and Biotechnologies, University of Bologna, Bologna, Italy.
authors: Daniela
authors: D
authors: Grifoni
authors: Department of Pharmacy and Biotechnologies, University of Bologna, Bologna, Italy.
authors: Annalisa
authors: A
authors: Pession
authors: Department of Molecular Medicine, University of Padova, Padua, Italy.
authors: Francesca
authors: F
authors: Zanconato
authors: Department of Biomedical Sciences, University of Padova, Padua, Italy.
authors: Giulia
authors: G
authors: Guzzo
authors: Department of Life Sciences, Center for Genome Research University of Modena and Reggio Emilia, Modena, Italy.
authors: Silvio
authors: S
authors: Bicciato
authors: Department of Molecular Medicine, University of Padova, Padua, Italy sirio.dupont@unipd.it.
authors: Sirio
authors: S
authors: Dupont
mesh_terms: D000217:Acyltransferases; D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000818:Animals; D001420:Bacteria, Aerobic / Q000378:metabolism*; D045744:Cell Line, Tumor; D047369:Chromatin Immunoprecipitation; D004330:Drosophila; D006019:Glycolysis / Q000235:genetics / Q000502:physiology; D006801:Humans; D047468:Immunoprecipitation; D010750:Phosphoproteins / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D014157:Transcription Factors / Q000378:metabolism*; D000091102:YAP-Signaling Proteins
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D010750:Phosphoproteins; D014157:Transcription Factors; D000091102:YAP-Signaling Proteins; C088374:YAP1 protein, human; D000217:Acyltransferases; C108675:TAFAZZIN protein, human
keywords: Hippo pathway; TEAD; YAP/TAZ; aerobic glycolysis; glucose metabolism