P4HA1/HIF1α feedback loop drives the glycolytic and malignant phenotypes of pancreatic cancer.

Hypoxia-inducible factor 1α (HIF1α) activation is profoundly implicated in the initiation and progression of multiple malignant tumors. Prolyl 4-hydroxylase subunit alpha 1 (P4HA1) is the active catalytic component of prolyl 4-hydroxylase and has been reported to promote tumor progression in several cancers. In this study, we revealed that P4HA1 was highly expressed in pancreatic ductal adenocarcinoma (PDAC) and predicted a poor clinical outcome. Notably, elevated expression of P4HA1 in PDAC cells was HIF1α-dependent. Gene set enrichment analysis of The Cancer Genome Atlas (TCGA) cohort demonstrated a close link between P4HA1 expression and glycolysis and hypoxia gene signatures in PDAC. Knockdown of P4HA1 significantly suppressed the glycolytic activity of PDAC cells as revealed by reduced glucose utilization and lactate production. Consistently, there was a close correlation between P4HA1 and glycolysis genes. Moreover, we found that P4HA1 can enhance HIF1α stability, indicating a positive feedback loop between HIF1α and P4HA1 in PDAC. Genetic silencing of P4HA1 significantly inhibited the cell proliferation, chemoresistance, and stemness of PDAC cells. Collectively, our findings identify the P4HA1-HIF1α loop as a critical regulator in glycolysis and oncogenic activities of PDAC and provide a potential target for pancreatic cancer treatment.