Non-canonical HIF-1 stabilization contributes to intestinal tumorigenesis

Rohwer, N. et al. (2019) Non-canonical HIF-1 stabilization contributes to intestinal tumorigenesis. Oncogene, 38(28), pp. 5670-5685. (doi: 10.1038/s41388-019-0816-4) (PMID:31043706)

Abstract

The hypoxia-inducible transcription factor HIF-1 is appreciated as a promising target for cancer therapy. However, conditional deletion of HIF-1 and HIF-1 target genes in cells of the tumor microenvironment can result in accelerated tumor growth, calling for a detailed characterization of the cellular context to fully comprehend HIF-1’s role in tumorigenesis. We dissected cell type-specific functions of HIF-1 for intestinal tumorigenesis by lineage-restricted deletion of the Hif1a locus. Intestinal epithelial cell-specific Hif1a loss reduced activation of Wnt/β-catenin, tumor-specific metabolism and inflammation, significantly inhibiting tumor growth. Deletion of Hif1a in myeloid cells reduced the expression of fibroblast-activating factors in tumor-associated macrophages resulting in decreased abundance of tumor-associated fibroblasts (TAF) and robustly reduced tumor formation. Interestingly, hypoxia was detectable only sparsely and without spatial association with HIF-1α, arguing for an importance of hypoxia-independent, i.e., non-canonical, HIF-1 stabilization for intestinal tumorigenesis that has not been previously appreciated. This adds a further layer of complexity to the regulation of HIF-1 and suggests that hypoxia and HIF-1α stabilization can be uncoupled in cancer. Collectively, our data show that HIF-1 is a pivotal pro-tumorigenic factor for intestinal tumor formation, controlling key oncogenic programs in both the epithelial tumor compartment and the tumor microenvironment.

• Item Type: Articles
• Additional Information: Research in the Cramer lab was supported by grants from Deutsche Krebshilfe (109160) and Deutsche Forschungsgemeinschaft (CR 133/2-1 until 2–4). NR was supported by a grant from the BMBF (MAPTor-NET (031A426A)).
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Faller, Dr William and Sansom, Professor Owen
• Authors: Rohwer, N., Jumpertz, S., Erdem, M., Egners, A., Warzecha, K. T., Fragoulis, A., Kühl, A. A., Kramann, R., Neuss, S., Rudolph, I., Endermann, T., Zasada, C., Apostolova, I., Gerling, M., Kempa, S., Hughes, R., Lewis, C. E., Brenner, W., Malinowski, M. B., Stockmann, M., Schomburg, L., Faller, W., Sansom, O. J., Tacke, F., Morkel, M., and Cramer, T.
• College/School: College of Medical Veterinary and Life Sciences > School of Cancer Sciences
• Journal Name: Oncogene
• Publisher: Springer Nature
• ISSN: 0950-9232
• ISSN (Online): 1476-5594
• Published Online: 01 May 2019