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Immortalization-upregulated protein (IMUP) plays a vital role in cell proliferation and tumor progression. However, its role in pancreatic ductal adenocarcinoma (PDAC) remains unclear. Here, we select  IMUP  as an alternative gene based on GeneChip analysis of clinical PDAC tissues and transcriptome data from The Cancer Genome Atlas.  IMUP  expression is upregulated in PDAC tumor tissues. Moreover, high  IMUP  expression correlates with poor prognosis, while  IMUP  depletion inhibits PDAC cell proliferation and colony formation capacity in vitro, and decreases xenograft tumor growth in vivo.  IMUP  downregulation leads to cell-cycle arrest in the S phase.  IMUP  knockdown increases the expression of four-and-a-half LIM domain protein 1 (FHL1), which regulates the phosphorylation of cell division cycle 25A (CDC25A) by cycle checkpoint kinase 1 (CHK1) and promotes cytoplasmic distribution of CDC25A by interaction with 14–3-3ξ. Furthermore,  FHL1  knockdown restores the effects induced by  IMUP  depletion. Liquid chromatography tandem mass spectrometry and immunoprecipitation analysis further show that  IMUP  interacts directly with nucleophosmin (NPM1) and enhances its stability. DNA methylation sequencing shows that  FHL1  promoter methylation decreases when  IMUP  is downregulated. Overexpression of  NPM1  can increase the methylation level of  FHL1 , thereby decreasing its expression. Our study provides a novel perspective on IMUP/NPM1/FHL1-mediated cell-cycle arrest by regulating CDC25A phosphorylation in PDAC. These findings may provide a new therapeutic target for PDAC. Graphical abstract

Immortalization-upregulated protein promotes pancreatic cancer progression by regulating NPM1/FHL1-mediated cell-cycle-checkpoint protein activity