Affiliation:
1. Barts Cancer Institute
2. University of Oxford
3. Barts Cancer Institute, QMUL
Abstract
Abstract
We have previously shown that expression of S100PBP, an S100P binding partner, gradually decreases during progression of pancreatic ductal adenocarcinomas (PDAC). Here, we show that loss of S100PBP leads to oncogenic transformation of pancreatic cells; after deregulation of S100PBP expression, both in silico and in vitro analyses highlighted alterations of genes known to modulate cytoskeleton, cell motility and survival. Overexpression of S100P reduced S100PBP expression, while co-immunoprecipitation indicated the interaction of S100P with S100PBP-p53-ubiquitin protein complex, likely causing S100PBP degradation. The doxycycline-induced KrasG12D activation resulted in decreased S100PBP levels, while low-dose treatment with HDAC inhibitor MS-275 rescued its expression in both human and mouse PDAC cell lines. This indicates KrasG12D as an upstream epigenetic regulator of S100PBP. Finally, analysis of TCGA PanCancer Atlas PDAC datasets demonstrated poor prognosis in patients with high S100P and low S100PBP expression, suggesting that S100PBP is a novel tumour suppressor gene with potential clinical utility.
Publisher
Research Square Platform LLC
Reference56 articles.
1. Expression of S100P and its novel binding partner S100PBPR in early pancreatic cancer;Dowen SE;Am J Pathol,2005
2. S100P-binding protein, S100PBP, mediates adhesion through regulation of cathepsin Z in pancreatic cancer Cells;Lines KE;Am J Pathol,2012
3. Identification of key genes and pathways at the downstream of S100PBP in pancreatic cancer cells by integrated bioinformatical analysis;Lu YJ;Transl Cancer Res,2021
4. Novel functions and targets of miR-944 in human cervical cancer cells;Xie H;Int J Cancer,2015
5. Genome-wide scan for copy number alteration association with relapse-free survival in colorectal cancer with liver metastasis patients;Yang PS;J Clin Med,2018