The VHL/HIF axis in clear cell renal carcinoma

Abstract

Inactivation of the VHL tumor suppressor protein (pVHL) is a common event in clear cell renal carcinoma, which is the most common form of kidney cancer. pVHL performs many functions, including serving as the substrate recognition module of an ubiquitin ligase complex that targets the alpha subunits of the heterodimeric HIF transcription factor for proteasomal degradation. Deregulation of HIF2α appears to be a driving force in pVHL-defective clear cell renal carcinomas. In contrast, genetic and functional studies suggest that HIF1α serves as a tumor suppressor and is a likely target of the 14q deletions that are characteristic of this tumor type. Drugs that inhibit HIF2α, or its downstream targets such as VEGF, are in various stages of clinical testing. Indeed, clear cell renal carcinomas are exquisitely sensitive to VEGF deprivation and four VEGF inhibitors have now been approved for the treatment of this disease.

Fig 1. Role of pVHL, HIF1α, and HIF2α in Clear Cell Carcinoma

Loss of pVHL leads to the accumulation of both HIF1α and HIF2α, which have opposing effects on clear cell carcinogenesis. The leads to selection pressure to downregulate HIF1α.

Fig 2. Quantitative differences between HIF1α and HIF2α related to activation of HIF target genes

HIF1α is more sensitive than HIF2α to inhibition by FIH1. Competitive displacement of HIF2α by HIF1α in a well-oxygenated pVHL-defective cell might therefore decrease the transcription of certain genes that are responsive to HIFα CTAD function.

Fig 3. Qualititative differences between HIF1α and HIF2α related to activation of HIF target genes

The genesets regulated by HIF1α and HIF2α overlap but are not entirely congruent. The former might be biased toward renal carcinoma suppressors and the latter to renal carcinoma oncoproteins.

Fig 4. Qualititative differences between HIF1α and HIF2α with respect to non-canonical HIF functions

HIF1α and HIF2α have opposing actions in some systems with respect to collateral signaling pathways involving cancer-relevant proteins such as c-Myc and p53.