Abstract 385: HIF1A can regulate Wnt signaling in human colon cancer cells

Abstract

Abstract Standard-of-care treatment for KRAS mutant metastatic colorectal cancer (mCRC) combines a cytotoxic chemotherapy backbone (FOLFOX) with an antiangiogenesis biologic agent (i.e., bevacizumab). Despite significant efforts to improve treatment, the prognosis for this type of cancer remains poor with an average 5-year overall survival of ~11%. Oncogenic KRAS mutations lead to the overactivation of RAS/ERK/MAPK pathwa,y driving many hallmarks of cancer such as cell proliferation, growth, and altered metabolism. In particular, several studies have shown that oncogenic activation of KRAS leads to normoxic stabilization of HIF1A protein, which can then reprogram cellular metabolism towards aerobic glycolysis. Our studies have discovered that overactive Wnt signaling can also reprogram cancer cell metabolism towards aerobic glycolysis. Of note, KRAS (~40%) and Wnt signaling (~90%) are very frequently coactivated in colorectal cancer. Interestingly, an important, key metabolic gene targeted by Wnt signaling, Pyruvate Dehydrogenase Kinase I (PDK1), is also directly regulated by HIF1A, suggesting there may be crosstalk between the HIF1A and Wnt pathways. Indeed, several published studies support the idea that HIF1A can influence Wnt signaling, and our data show this may occur through regulation of the Wnt mediating transcription factors LEF1 and TCF1 (TCF7 gene). Using luciferase reporters driven by LEF/TCF promoters, we observed significantly increased LEF1/TCF7 promoter activity in hypoxic colon cancer cells but not for other TCF family members (TCF7L1/TCF7L2). We identified putative hypoxia responsive elements (HREs) in the human LEF1 promoter, and deletion of these HREs reduced responsiveness to hypoxia. Furthermore, we have found that targeting glycolysis and Wnt can be synergistic in inhibiting colon cancer cell colony growth. We find that HIF1A and LEF/TCF/beta-catenin complexes coregulate gene expression of metabolic targets as well as Wnt signaling components (e.g., LEF1 and TCF7). These data suggest that cross-regulation between the HIF1A and Wnt signaling pathway is important and may be a potential Achilles heel for novel therapeutics in targeting KRAS mutant colon cancer. Current studies are under way to further investigate the mechanisms of crosstalk and joint regulation of metabolic reprogramming in KRAS mutant colon cancer cells. Citation Format: Yung Lyou, George Chen, Marian Waterman. HIF1A can regulate Wnt signaling in human colon cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 385.