Pancreatic cancers suppress negative feedback of glucose transport to reprogram chromatin for metastasis

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
2020 Nature Communications  
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
more » ... ic 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.
doi:10.1038/s41467-020-17839-5 pmid:32792504 fatcat:yp5qwhemvbfxtfolyqlovsjnhu