BAG-1 suppresses expression of the key regulatory cytokine transforming growth factor β (TGF-β1) in colorectal tumour cells

Skeen, V. R.; Collard, T. J.; Southern, S. L.; Hague, A.; Townsend, P. A.; Paraskeva, C.; Williams, A. C.; Skeen, Victoria R; Collard, Tracey J; Southern, Samantha L; Hague, Angela; Townsend, Paul; Paraskeva, Chris; Williams, Ann C; Greenhough, A.

Abstract

As colorectal cancer remains the second highest cause of cancer-related deaths in much of the industrialised world, identifying novel strategies to prevent colorectal tumour development remains an important challenge. BAG-1 is a multi-functional protein, the expression of which is up-regulated at relatively early stages in colorectal tumorigenesis. Importantly, BAG-1 is thought to enhance colorectal tumour progression through promoting tumour cell survival. Here, we report for the first time a novel role for BAG-1, establishing it as a suppressor of transforming growth factor β (TGF-β1) expression in colorectal tumour cells. Microarray analysis first highlighted the possibility that BAG-1 may regulate TGF-β1 expression, a key cytokine in normal colonic tissue homoeostasis. Q-RT-PCR and ELISA demonstrated TGFB1 mRNA and protein expression to be significantly increased when BAG1 levels were reduced by small interfering RNA; additionally, induction of BAG-1L caused suppression of TGFB1 mRNA in colorectal tumour cells. Using reporter and chromatin immunoprecipitation assays, a direct association of BAG-1 with the TGFB1 gene regulatory region was identified. Immunohistochemistry and Weiser fraction data indicated that the levels of BAG-1 and TGF-β1 are inversely correlated in the normal colonic epithelium in vivo, consistent with a role for BAG-1-mediated repression of TGF-β1 production. In vitro studies showed that the change in TGF-β1 production following manipulation of BAG-1 is functionally relevant; through induction of anchorage-independent growth in TGF-β1-dependent normal rat kidney fibroblasts and regulation of SMAD2 phosphorylation in TGF-β1-sensitive adenoma cells. Taken together, this study identifies the anti-apoptotic protein BAG-1 as a suppressor of the inhibitory growth factor TGF-β1, suggesting that high expression of BAG-1 can impact on a number of the hallmarks of cancer, of potential importance in promoting the early stages of colorectal tumorigenesis. Establishing BAG-1 as a repressor of TGF-β1 has important biological implications, and highlights a new role for BAG-1 in colorectal tumorigenesis. © 2013 Macmillan Publishers Limited.

• Journal Article Type: Article
• Acceptance Date: Sep 2, 2012
• Online Publication Date: Oct 29, 2012
• Publication Date: Sep 19, 2013
• Journal: Oncogene
• Print ISSN: 0950-9232
• Electronic ISSN: 1476-5594
• Publisher: Springer Nature [academic journals on nature.com]
• Peer Reviewed: Peer Reviewed
• Volume: 32
• Issue: 38
• Pages: 4490-4499
• DOI: https://doi.org/10.1038/onc.2012.480
• Public URL: https://uwe-repository.worktribe.com/output/927685
• Publisher URL: https://doi.org/10.1038/onc.2012.480