Pancreatic cancers suppress negative feedback of glucose transport to reprogram chromatin for metastasis
| Autor: | Anna E Word, Matthew E. Bechard, Yi Zhong, Amanda V. Tran, Sydney L. Campbell, Oliver G. McDonald, Akimasa Hayashi, Vivian L. Weiss, Christine A. Iacobuzio-Donahue, Rana V Smalling, Kathryn E. Wellen |
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| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Chromatin Immunoprecipitation Science Mice Nude General Physics and Astronomy Cell Cycle Proteins 02 engineering and technology medicine.disease_cause Article General Biochemistry Genetics and Molecular Biology Metastasis Epigenesis Genetic Mice 03 medical and health sciences Thioredoxins Glucose import medicine Animals lcsh:Science Multidisciplinary biology Phosphogluconate Dehydrogenase Glucose transporter Biological Transport Pancreatic cancer General Chemistry respiratory system Cellular Reprogramming 021001 nanoscience & nanotechnology Cancer metabolism Chromatin Pancreatic Neoplasms Glucose 030104 developmental biology Histone Cancer research biology.protein lipids (amino acids peptides and proteins) lcsh:Q Carrier Proteins 0210 nano-technology Carcinogenesis Chromatin immunoprecipitation Reprogramming TXNIP |
| Zdroj: | Nature Communications, Vol 11, Iss 1, Pp 1-14 (2020) Nature Communications |
| ISSN: | 2041-1723 |
| Popis: | Although metastasis is the most common cause of cancer deaths, metastasis-intrinsic dependencies remain largely uncharacterized. We previously reported that metastatic pancreatic cancers were dependent on the glucose-metabolizing enzyme phosphogluconate dehydrogenase (PGD). Surprisingly, PGD catalysis was constitutively elevated without activating mutations, suggesting a non-genetic basis for enhanced activity. Here we report a metabolic adaptation that stably activates PGD to reprogram metastatic chromatin. High PGD catalysis prevents transcriptional up-regulation of thioredoxin-interacting protein (TXNIP), a gene that negatively regulates glucose import. This allows glucose consumption rates to rise in support of PGD, while simultaneously facilitating epigenetic reprogramming through a glucose-fueled histone hyperacetylation pathway. Restoring TXNIP normalizes glucose consumption, lowers PGD catalysis, reverses hyperacetylation, represses malignant transcripts, and impairs metastatic tumorigenesis. We propose that PGD-driven suppression of TXNIP allows pancreatic cancers to avidly consume glucose. This renders PGD constitutively activated and enables metaboloepigenetic selection of additional traits that increase fitness along glucose-replete metastatic routes. Distant metastases from pancreatic cancer patients were previously reported by the authors to be dependent on the glucose-metabolizing enzyme phosphogluconate dehydrogenase (PGD). Here the authors report a novel metabolic adaptation that that stably activates PGD to reprogram metastatic chromatin. |
| Databáze: | OpenAIRE |
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