Pancreatic cancers suppress negative feedback of glucose transport to reprogram chromatin for metastasis Journal Article
| Authors: | Bechard, M. E.; Smalling, R.; Hayashi, A.; Zhong, Y.; Word, A. E.; Campbell, S. L.; Tran, A. V.; Weiss, V. L.; Iacobuzio-Donahue, C.; Wellen, K. E.; McDonald, O. G. |
| Article Title: | Pancreatic cancers suppress negative feedback of glucose transport to reprogram chromatin for metastasis |
| Abstract: | 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. © 2020, The Author(s). |
| Keywords: | controlled study; protein expression; histopathology; nonhuman; pancreas cancer; animal cell; chromosome; mouse; phenotype; animal tissue; gene expression; confocal microscopy; animal experiment; protein; small interfering rna; rna interference; enzyme activity; histology; carcinogenesis; cell culture; chromatin; chromatin immunoprecipitation; immunoprecipitation; blood transfusion; glucose; upregulation; fitness; immunofluorescence test; catalysis; negative feedback; tumor growth; autopsy; biochemistry; glucose intake; glucose transport; rna extraction; trichostatin a; metabolomics; pancreas metastasis; glucose transporter 4; transcription factor nrf2; histone acetylation; cancer; human; article |
| Journal Title: | Nature Communications |
| Volume: | 11 |
| ISSN: | 2041-1723 |
| Publisher: | Nature Publishing Group |
| Date Published: | 2020-08-13 |
| Start Page: | 4055 |
| Language: | English |
| DOI: | 10.1038/s41467-020-17839-5 |
| PUBMED: | 32792504 |
| PROVIDER: | scopus |
| PMCID: | PMC7426874 |
| DOI/URL: | |
| Notes: | Article -- Source: Scopus |
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