TY  - GEN
AV  - public
Y1  - 2015///
TI  - Transcriptional co-regulators TBL1X and TBL1XR1 control tumor growth and tumor cell metabolism in pancreatic cancer
ID  - heidok18003
A1  - Stoy, Christian
UR  - https://archiv.ub.uni-heidelberg.de/volltextserver/18003/
N2  - Pancreatic ductal adenocarcinoma (PDAC) is among the ten most frequent cancers in the western world, and also one of the most lethal. The mortality rate approximately equals the incidence rate and the five-year survival rate is only around 5%, mainly due to advanced stage at diagnosis, non-resectability, and frequent chemotherapy resistance. Epidemiological studies show that obesity and/or type 2 diabetes increase the risk of PDAC. Both conditions have been increasing world wide during the last 20?30 years, and have become a global health hazard.

The transcriptional co-regulators TBL1X (transducin-beta-like 1, X-linked) and TBL1XR1 (transducin-beta-like 1X-related protein 1) mediate the exchange of co-repressors to co-activators on target gene promoters. They have been shown by previous work in our lab to regulate lipid metabolism in liver and white adipose tissue. Furthermore, they interact with Wnt/?-catenin signaling, a pathway frequently altered in cancers. Recent studies have shown a growth-regulating role of TBL1XR1 in various cancer entities, but not in pancreatic cancer.

The aim of the present study was therefore to investigate whether TBL1X and/or TBL1XR1 play a role in pancreatic cancer and might link tumor initiation or progression with obesity or type 2 diabetes.
While the latter could not be confirmed, the present study was able to show that TBL1X and TBL1XR1 were highly expressed in human and murine pancreatic cancer. The expression was specific for PanIN precursor lesions and carcinoma cells, while healthy tissue showed little to no expression. In human patients, multiple genes involved in metabolic processes showed a high correlation with TBL1X and TBL1XR1 expression. In vitro studies revealed a growth-promoting effect of TBL1X and TBL1XR1 in pancreatic cancer cells and gene expression microarrays indicated cell cycle and p53 signaling as the most prominently regulated pathways. Furthermore, both proteins, especially TBL1X, affected tumor cell glucose metabolism and cellular response to glucose withdrawal.
Application of a syngeneic subcutaneous allograft mouse model confirmed the growth-regulating effect of Tbl1x in vivo. Ablation of Tbl1x additionally sensitized murine Panc02 tumor cells to gemcitabine, the most commonly used chemotherapeutic agent for pancreatic cancer. Tbl1x-deficient cells had markedly reduced levels of PI3 kinase, a major regulator of cell growth and metabolism, as well as downstream mediators. TBL1X was confirmed to bind to PI3 kinase promoter region and its expression correlated with PI3 kinase in human patients.

Taken together, this study is the first to show a role of TBL1X in cancer, and of TBL1XR1 in pancreatic cancer, both in humans and in mice. The control of PI3 kinase by TBL1X on the transcriptional level is a plausible explanation for the observed sensitization to gemcitabine, making TBL1X an attractive target for future cancer therapies to enhance treatment response and patient survival.
ER  -