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

EMBO Molecular Medicine

Christian Stoy⁴  Aishwarya Sundaram⁴  Marcos Rios Garcia⁴  Xiaoyue Wang⁴  Oksana Seibert⁴  Annika Zota⁴  Susann Wendler²  David Männle²  Ulf Hinz²  Carsten Sticht³  Maria Muciek³  Norbert Gretz³  Adam J Rose⁴  Vera Greiner⁶  Thomas G. Hofmann⁶  Andrea Bauer⁵  Jörg Hoheisel⁵  Mauricio Berriel Diaz⁴  Matthias M Gaida¹  Jens Werner²  Tobias Schafmeier⁴  Oliver Strobel² 

[1] Institute of Pathology, Heidelberg University, Heidelberg, Germany;Department of General Surgery, University Hospital Heidelberg, Heidelberg, Germany;Medical Research Center, Klinikum Mannheim, Mannheim, Germany;Joint Division Molecular Metabolic Control, German Cancer Research Center (DKFZ) Heidelberg, Center for Molecular Biology (ZMBH) and University Hospital, Heidelberg University, Heidelberg, Germany;Functional Genome Analysis, German Cancer Research Center (DKFZ) Heidelberg, Heidelberg, Germany;Research Group Cellular Senescence, German Cancer Research Center (DKFZ) Heidelberg, Heidelberg, Germany

关键词: gemcitabine;    pancreatic cancer;    PI3 kinase;    TBL1;    tumor metabolism;   

DOI  :  10.15252/emmm.201404837

来源: Wiley

【 摘 要 】

Abstract

Pancreatic 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.

Synopsis

The 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.

【 授权许可】

CC BY   
© 2015 The Authors. Published under the terms of the CC BY 4.0 license

Creative Commons Attribution 4.0 License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.