Abstract
The principle factors underlying gastric cancer (GC) development and outcomes are not well characterized resulting in a paucity of validated therapeutic targets. To identify potential molecular targets, we analyze gene expression data from GC patients and identify the nuclear receptor ESRRG as a candidate tumor suppressor. ESRRG expression is decreased in GC and is a predictor of a poor clinical outcome. Importantly, ESRRG suppresses GC cell growth and tumorigenesis. Gene expression profiling suggests that ESRRG antagonizes Wnt signaling via the suppression of TCF4/LEF1 binding to the CCND1 promoter. Indeed, ESRRG levels are found to be inversely correlated with Wnt signaling-associated genes in GC patients. Strikingly, the ESRRG agonist DY131 suppresses cancer growth and represses the expression of Wnt signaling genes. Our present findings thus demonstrate that ESRRG functions as a negative regulator of the Wnt signaling pathway in GC and is a potential therapeutic target for this cancer.
Highlights
Gastrointestinal (GI) cancers are among the most common cancers worldwide[1]
We focused on transcription factors (TFs) for further analysis as they are the regulatory endpoints of signaling pathways and their deregulation is commonly linked to cancer development[7]
We focused on elucidating the function of estrogen-related receptor gamma (ESRRG) in gastric cancer (GC)
Summary
Gastrointestinal (GI) cancers are among the most common cancers worldwide[1]. Among GI cancers, gastric cancer (GC) is the predominant cause of mortality in Asian populations[1]. Molecular therapeutics have been implemented to target GC. These include trastuzumab, which targets HER2, and bevacizumab, which targets VEGF-A3. TP53 and RUNX3 function as transcription factors (TFs) and confer tumor suppressive activity by antagonizing diverse oncogenic pathways including the Wnt and TGF-β pathways. We identified estrogen-related receptor gamma (ESRRG; known as ERRγ) as a potential tumor suppressor in GC by genomic analysis. Genomic profiling analysis revealed that, similar to other tumor suppressor genes in GC, ESRRG suppresses the Wnt signaling pathway. Our present study provides new insights into the molecular mechanisms in GC, and suggests that activation of ESRRG by antagonizing Wnt signaling through compounds such as DY131 could provide a novel therapeutic approach to treating this cancer
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