Abstract 5494: Hypoxia via HIF1alpha can regulate Wnt signaling in human colon cancer cells

Standard-of-care treatment for metastatic colorectal cancer combines chemotherapy with bevacizumab, an angiogenesis inhibitor that depletes nutrients and triggers hypoxia. Unfortunately, this strategy extends patient survival only a few months because tumors acquire adaptive resistance, enabling resumption of angiogenesis. Adaptive resistance arises from reprogrammed metabolism, but the regulatory networks that govern reprogramming are not defined. Our studies have shown that overactive Wnt signaling, which is the most common cause of colon cancer, programs cancer metabolism by promoting glycolysis and angiogenesis. Interestingly, metabolic genes targeted by Wnt are also regulated by the hypoxia transcription factor HIF1alpha suggesting there may be crosstalk between the two pathways. Several studies suggest that HIF1alpha can influence Wnt signaling, but the reported effects are variable ranging from positive to negative. We find that HIF1alpha and LEF/TCF/beta-catenin complexes co-regulate metabolic targets including LEF1 and TCF1 (TCF7) expression. Using luciferase reporters driven by LEF/TCF promoters, we observe significantly increased LEF1/TCF1 but not TCF3(TCF7L1)/TCF4(TCF7L2) promoter activity in hypoxic colon cancer cells. We identified putative hypoxia responsive elements (HREs) in the human LEF1 promoter and deletion of these HREs reduced responsiveness to hypoxia. Furthermore, when colon cancer cells were treated with inhibitors that either inactivate or reduce HIF1alpha protein, there was a significant decrease in Wnt reporter activity. These results suggest that hypoxia and the Wnt pathway crosstalk wherein hypoxia co-regulates metabolism genes and increases Wnt signaling capacity via LEF/TCF expression. Current studies are underway to investigate the mechanisms of crosstalk and joint regulation of metabolic gene programs during adaptive resistance. Citation Format: Yung Lyou, Amber Habowski, Stephanie Sprowl-Tanio, Kira Pate, George Chen, Marian L. Waterman. Hypoxia via HIF1alpha can regulate Wnt signaling in human colon cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5494. doi:10.1158/1538-7445.AM2017-5494