Glucose deprivation promotes pseudo-hypoxia and de-differentiation in lung adenocarcinoma.

Autor:	Saggese P; Division of Pulmonary Medicine, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA., Pandey A; Division of Pulmonary Medicine, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA., Fung E; Division of Pulmonary Medicine, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA.; Division of Thoracic Surgery, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA., Hall A; Division of Pulmonary Medicine, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA., Yanagawa J; Division of Thoracic Surgery, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA., Rodriguez EF; Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA., Grogan TR; Division of General Internal Medicine and Health Services Research, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA., Giurato G; Laboratory of Molecular Medicine and Genomics, Department of Medicine, Surgery and Dentistry 'Scuola Medica Salernitana', University of Salerno, Baronissi (SA), Italy.; Genome Research Center for Health - CRGS, Campus of Medicine of the University of Salerno, Baronissi (SA), Italy., Nassa G; Laboratory of Molecular Medicine and Genomics, Department of Medicine, Surgery and Dentistry 'Scuola Medica Salernitana', University of Salerno, Baronissi (SA), Italy.; Genome Research Center for Health - CRGS, Campus of Medicine of the University of Salerno, Baronissi (SA), Italy., Salvati A; Laboratory of Molecular Medicine and Genomics, Department of Medicine, Surgery and Dentistry 'Scuola Medica Salernitana', University of Salerno, Baronissi (SA), Italy.; Genome Research Center for Health - CRGS, Campus of Medicine of the University of Salerno, Baronissi (SA), Italy.; Medical Genomics Program and Division of Onco-Hematology, AOU 'S. Giovanni di Dio e Ruggi d'Aragona', University of Salerno, Salerno, Italy., Weisz A; Laboratory of Molecular Medicine and Genomics, Department of Medicine, Surgery and Dentistry 'Scuola Medica Salernitana', University of Salerno, Baronissi (SA), Italy.; Genome Research Center for Health - CRGS, Campus of Medicine of the University of Salerno, Baronissi (SA), Italy.; Medical Genomics Program and Division of Onco-Hematology, AOU 'S. Giovanni di Dio e Ruggi d'Aragona', University of Salerno, Salerno, Italy., Dubinett SM; Division of Pulmonary Medicine, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA.; Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA.; Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA., Scafoglio C; Division of Pulmonary Medicine, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA.
Jazyk:	angličtina
Zdroj:	BioRxiv : the preprint server for biology [bioRxiv] 2023 Feb 01. Date of Electronic Publication: 2023 Feb 01.
DOI:	10.1101/2023.01.30.526207
Abstrakt:	Increased utilization of glucose is a hallmark of cancer. Several studies are investigating the efficacy of glucose restriction by glucose transporter blockade or glycolysis inhibition. However, the adaptations of cancer cells to glucose restriction are unknown. Here, we report the discovery that glucose restriction in lung adenocarcinoma (LUAD) induces cancer cell de-differentiation, leading to a more aggressive phenotype. Glucose deprivation causes a reduction in alpha-ketoglutarate (αKG), leading to attenuated activity of αKG-dependent histone demethylases and histone hypermethylation. We further show that this de-differentiated phenotype depends on unbalanced EZH2 activity, causing inhibition of prolyl-hydroxylase PHD3 and increased expression of hypoxia inducible factor 1α (HIF1α), triggering epithelial to mesenchymal transition. Finally, we identified an HIF1α-dependent transcriptional signature with prognostic significance in human LUAD. Our studies further current knowledge of the relationship between glucose metabolism and cell differentiation in cancer, characterizing the epigenetic adaptation of cancer cells to glucose deprivation and identifying novel targets to prevent the development of resistance to therapies targeting glucose metabolism. Competing Interests: Declaration of Interests. The authors declare no conflicts of interest.
Databáze:	MEDLINE
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