Unknown

Dataset Information

0

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.

SUBMITTER: Bechard ME 

PROVIDER: S-EPMC7426874 | biostudies-literature | 2020 Aug

REPOSITORIES: biostudies-literature

altmetric image

Publications

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

Bechard Matthew E ME   Smalling Rana R   Hayashi Akimasa A   Zhong Yi Y   Word Anna E AE   Campbell Sydney L SL   Tran Amanda V AV   Weiss Vivian L VL   Iacobuzio-Donahue Christine C   Wellen Kathryn E KE   McDonald Oliver G OG  

Nature communications 20200813 1


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 metastat  ...[more]

Similar Datasets

| S-EPMC6925134 | biostudies-literature
| S-EPMC5567863 | biostudies-literature
| S-EPMC3741507 | biostudies-literature
| S-EPMC10014883 | biostudies-literature
| S-EPMC7308463 | biostudies-literature
| S-EPMC3009760 | biostudies-literature
| S-EPMC5293492 | biostudies-literature
| S-EPMC7004534 | biostudies-literature
| S-EPMC10067390 | biostudies-literature
| S-EPMC4412443 | biostudies-literature