Transcriptional co‐factor Transducin beta‐like (TBL) 1 acts as a checkpoint in pancreatic cancer malignancy

摘要

AbstractPancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer fatalities in Western societies, characterized by high metastatic potential and resistance to chemotherapy. Critical molecular mechanisms of these phenotypical features still remain unknown, thus hampering the development of effective prognostic and therapeutic measures in PDAC. Here, we show that transcriptional co-factor Transducin beta-like (TBL) 1 was over-expressed in both human and murine PDAC. Inactivation of TBL1 in human and mouse pancreatic cancer cells reduced cellular proliferation and invasiveness, correlating with diminished glucose uptake, glycolytic flux, and oncogenic PI3 kinase signaling which in turn could rescue TBL1 deficiency-dependent phenotypes. TBL1 deficiency both prevented and reversed pancreatic tumor growth, mediated transcriptional PI3 kinase inhibition, and increased chemosensitivity of PDAC cells in vivo. As TBL1 mRNA levels were also found to correlate with PI3 kinase levels and overall survival in a cohort of human PDAC patients, TBL1 was identified as a checkpoint in the malignant behavior of pancreatic cancer and its expression may serve as a novel molecular target in the treatment of human PDAC.SynopsisThe transcriptional co-factor TBL1, with known functions in liver and adipose tissue, is shown to be an oncogenic driver in pancreatic cancer. TBL1 inactivation curbs cancer growth and aggressiveness and regulates PI3 kinase in vitro and in vivo.The transcriptional co-factor TBL1 is highly overexpressed in pancreatic ductal adenocarcinoma.TBL1 controls pancreatic tumor cell proliferation and invasion.The p110α subunit of PI3 kinase is a direct transcriptional target of TBL1.TBL1 inhibition reduces pancreatic tumor size and enhances sensitivity to gemcitabine in vivo.