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.

• Authors: Matthew E Bechard, Rana Smalling, Akimasa Hayashi, Yi Zhong, Anna E Word, Sydney L Campbell, Amanda V Tran, Vivian L Weiss, Christine Iacobuzio-Donahue, Kathryn E Wellen, Oliver G McDonald
• Journal: Nature communications (Nat Commun) Vol. 11 Issue 1 Pg. 4055 (08 13 2020) ISSN: 2041-1723 [Electronic] England
• PMID: 32792504 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Carrier Proteins
• Cell Cycle Proteins
• Chromatin
• Txnip protein, mouse
• Thioredoxins
• Phosphogluconate Dehydrogenase
• Glucose

Topics

• Animals
• Biological Transport (genetics, physiology)
• Carrier Proteins (genetics, metabolism)
• Cell Cycle Proteins (genetics, metabolism)
• Cellular Reprogramming (genetics, physiology)
• Chromatin (metabolism)
• Chromatin Immunoprecipitation
• Epigenesis, Genetic (genetics)
• Glucose (metabolism)
• Mice
• Mice, Nude
• Pancreatic Neoplasms (genetics, metabolism, pathology)
• Phosphogluconate Dehydrogenase (genetics, metabolism)
• Thioredoxins (genetics, metabolism)