Kidney cancers often delete chromosome 3p, spanning the VHL tumor suppressor gene, and chromosome 14q, which presumably harbors one or more tumor suppressor genes. pVHL inhibits the HIF transcription factor and HIF2α is a kidney cancer oncoprotein. Here we identify focal, homozygous, deletions of the HIF1α locus on 14q in clear cell renal carcinoma cell lines. Wild-type HIF1α, but not the products of these altered loci, suppress renal carcinoma growth. Conversely, downregulation of HIF1α in HIF1α-proficient lines promote tumor growth. HIF1α activity is diminished in 14q deleted kidney cancers and all of the somatic HIF1α mutations identified in kidney cancers tested to date are loss of function. Therefore HIF1α has the credentials of a kidney cancer suppressor gene.

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.