PPP3CB inhibits pancreatic cancer progression via promoting translocation of ATOH8 and further transcriptionally regulating Sp1

Abstract Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal malignancy which lacks effective therapeutic targets. We previously demonstrated that low expression level of PPP3CB was correlated with poor prognosis in PDAC but its function and mechanism remain to be elucidated. Here, we found that the expression of PPP3CB was higher in PDAC patients with early stage than that in late stage. PPP3CB overexpression impaired proliferation and metastatic ability of PDAC both in vitro and in vivo, whereas its depletion or the treatment of CsA, a PPP3CB inhibitor, had the opposite effect. Liquid chromatography-tandem mass spectrometry and bioinformatic analysis predicted the protein interaction between PPP3CBand ATOH8. PPP3CB interacts with ATOH8 and increases its translocation into the nuclei of PDAC cells. ChIP-seq and luciferase analysis showed that ATOH8 can bind to the promoter of Sp1, a well-known oncogenic transcription factor in PDAC. Furthermore, PPP3CB transcriptionally inhibits Sp1 expression and pancreatic cancer metastases by enhancing ATOH8 nuclear content. These findings suggest a novel role for PPP3CB in preventing progression of PDAC by promoting the nuclear translocation of ATOH8 and transcriptionally inhibiting Sp1 expression. Consequently, PPP3CB emerges as a potential therapeutic target for PDAC.