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

Area of Science:

• Metabolic pathways in cancer
• Epigenetics and gene regulation
• Cancer metastasis mechanisms

Background:

• Metastasis is a leading cause of cancer mortality, yet its intrinsic dependencies are poorly understood.
• Metastatic pancreatic cancers were previously found to rely on phosphogluconate dehydrogenase (PGD).
• Elevated PGD activity in these cancers occurs without genetic mutations, suggesting non-genetic regulation.

Purpose of the Study:

• To investigate the non-genetic mechanisms stabilizing PGD activity in metastatic pancreatic cancer.
• To elucidate how enhanced PGD activity contributes to epigenetic reprogramming and metastasis.
• To explore therapeutic strategies targeting this metabolic adaptation.

Main Methods:

• Analysis of PGD catalysis and its regulation by TXNIP.
• Investigation of glucose import and consumption rates.
• Assessment of histone acetylation and gene expression changes.
• Evaluation of TXNIP restoration effects on metastasis in vivo.

Main Results:

• High PGD catalysis prevents thioredoxin-interacting protein (TXNIP) upregulation, increasing glucose uptake.
• This metabolic shift fuels histone hyperacetylation, leading to epigenetic reprogramming.
• Restoring TXNIP normalized glucose consumption, reduced PGD activity, reversed hyperacetylation, and inhibited metastasis.
• PGD-driven TXNIP suppression enables aggressive glucose consumption and promotes metastatic fitness.

Conclusions:

• Metastatic pancreatic cancers utilize a metabolic adaptation involving PGD and TXNIP to reprogram chromatin.
• This PGD-driven metaboloepigenetic reprogramming enhances glucose avidity and metastatic potential.
• Targeting the PGD-TXNIP axis offers a potential therapeutic strategy against pancreatic cancer metastasis.