HIF-2α release and HIF-interactions in tubular cells and clear cell renal cell carcinoma

• Applicant: Johannes Schödel, Ph.D.
• Subject Area: Nephrology ; Hematology, Oncology ; Reproductive Medicine, Urology
• Term: since 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 467519218

Clear cell renal cell carcinoma (ccRCC) is the most common subtype of renal cancer, accounting for more than 70% of kidney tumors. Mutation of the von Hippel-Lindau (VHL) gene in renal tubular cells has been identified as the truncal event in renal cancer evolution with first hits often occurring as early as in the second decade of life. Patients with VHL syndrome carry an inherited mutation in one VHL allele and acquire additional mutations in the second allele during life. Depending on the underlying first mutation this can dramatically increase the risk of developing ccRCC and additional tumors which characterize this syndrome including pheochromocytomas, hemangioblastomas, and retinal angiomas. Loss of VHL leads to stabilization of hypoxia inducible transcription factors (HIF) and triggers their transcriptional activity. The HIF-2α isoform is expressed de novo in VHL-defective tubular cells and appears to have an oncogenic role in the context of ccRCC. Genome-wide association studies have identified polymorphisms in non-protein coding regions in the HIF-2α gene locus. These polymorphisms modify the risk of developing renal cancer. This suggests that transcriptional dysregulation contributes substantially to the release of HIF-2α expression and tumor formation. Our preliminary observations indicate that HIF can regulate the mRNA expression of HIF-2α via direct DNA interactions at the HIF-2α locus in non-transformed renal tubular cells. However, the repertoire of regulatory elements and transcription factors contributing to this expression and modulating the epigenetic landscape at this genomic locus is unclear. It seems also plausible that RCC-associated SNPs in this region may interact with HIF-signalling to promote HIF-2α expression. We will employ high-end sequencing and cell culture technology to exactly define epigenetic dynamics of HIF-2α regulation in renal tubular cells, early cancerous lesions and progressed tumors, thereby identifying novel mechanistic insights into oncogenic HIF-2α expression. We will resort to a large biobank of tissue specimens as well as primary renal tubular and cancer cells to perform our analyses. Furthermore, we plan to modify HIF-signalling in tubular cells isolated from the urine of patients with VHL-syndrome to model early steps of renal cancer evolution.Given the current clinical evaluation of HIF-2α inhibitors for the treatment of VHL-associated renal cancer, a comprehensive molecular analysis of epigenetic changes, is needed. The proposed work will carefully define mechanisms that manipulate expression of HIF-2α during early renal cancer development. It will provide a paradigm for a detailed mechanistic analysis of the regulation of a tumor promoter by integrating inherited and stage specific genetic and epigenetic events.

• DFG Programme: Research Grants
• International Connection: United Kingdom
• Cooperation Partner: Professor Dr. Peter J Ratcliffe