1. Transcriptomics and Metabolomics Integration Reveals Redox-Dependent Metabolic Rewiring in Breast Cancer Cells
- Author
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Paola Paci, Marco Vanoni, Tatiana Volpari, Fabrizia Mastroianni, Stefano D'Errico, Valentina Bravatà, Anna Maria Colangelo, Marcella Bonanomi, Daniela Gaglio, Lilia Alberghina, Manuela Scorza, Federica Conte, Giulia Fiscon, Noemi Salmistraro, Elenio Avolio, Gennaro Piccialli, Giusi Irma Forte, Bonanomi, M., Salmistraro, N., Fiscon, G., Conte, F., Paci, P., Bravata, V., Forte, G. I., Volpari, T., Scorza, M., Mastroianni, F., D'Errico, S., Avolio, E., Piccialli, G., Colangelo, A. M., Vanoni, M., Gaglio, D., Alberghina, L., Bonanomi, M, Salmistraro, N, Fiscon, G, Conte, F, Paci, P, Bravata, V, Forte, G, Volpari, T, Scorza, M, Mastroianni, F, D'Errico, S, Avolio, E, Piccialli, G, Colangelo, A, Vanoni, M, Gaglio, D, and Alberghina, L
- Subjects
Pyruvate decarboxylation ,Cancer metabolic rewiring ,CtBP2 ,Epigenetics ,Metabolomics integration ,Transcriptomics ,Cancer Research ,epigenetics ,Chemistry ,cancer metabolic rewiring ,transcriptomics ,metabolomics integration ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,Epigenetic ,Metabolism ,Article ,Cell biology ,Oncology ,Transcriptomic ,Anaerobic glycolysis ,Cancer cell ,Glycolysis ,NAD+ kinase ,Reprogramming ,RC254-282 - Abstract
Simple Summary Metabolic rewiring fuels cancer proliferation by enhanced glycolysis and the increased NADH/NAD+ ratio. In this study, we highlight the critical role of NADH in the epigenetic landscape mediated by CtBP2 (C-terminal binding protein 2) activation, linking metabolism to epigenetic transcriptional reprogramming. Moreover, using metabolomics and transcriptomics integration, we show that genetic and pharmacological down-regulation of CtBP2 strongly reduces cell proliferation by modulating the redox balance, nucleotide synthesis, reactive oxygen species (ROS) generation, and scavenging. Therefore, we provide evidence that metabolic rewiring plasticity regulates the crosstalk between metabolism and the transcriptional program that sustains energetic and anabolic demands in cancer cells. Abstract Rewiring glucose metabolism toward aerobic glycolysis provides cancer cells with a rapid generation of pyruvate, ATP, and NADH, while pyruvate oxidation to lactate guarantees refueling of oxidized NAD+ to sustain glycolysis. CtPB2, an NADH-dependent transcriptional co-regulator, has been proposed to work as an NADH sensor, linking metabolism to epigenetic transcriptional reprogramming. By integrating metabolomics and transcriptomics in a triple-negative human breast cancer cell line, we show that genetic and pharmacological down-regulation of CtBP2 strongly reduces cell proliferation by modulating the redox balance, nucleotide synthesis, ROS generation, and scavenging. Our data highlight the critical role of NADH in controlling the oncogene-dependent crosstalk between metabolism and the epigenetically mediated transcriptional program that sustains energetic and anabolic demands in cancer cells.
- Published
- 2021
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