Inhibition of HIF2α Is Sufficient to Suppress pVHL-Defective Tumor Growth

By K. Kondo, William Y. Kim, Mirna Lechpammer, W. Kaelin. PLoS Biology, 2003

641 citations recorded by the source corpus.

Biallelic inactivation of the von Hippel–Lindau tumor suppressor gene (VHL) is linked to the development of hereditary (VHL-associated) and sporadic clear-cell renal carcinomas as well as other abnormalities. The VHL gene product, pVHL, is part of an E3 ubiquitin ligase complex that targets the α subunits of the heterodimeric transcription factor HIF (hypoxia-inducible factor) for degradation in the presence of oxygen. Here we report that a HIF2α variant lacking both of its two prolyl hydroxylation/pVHL-binding sites prevents tumor inhibition by pVHL in a DNA-binding dependent manner. Conversely, downregulation of HIF2α with short hairpin RNAs is sufficient to suppress tumor formation by pVHL-defective renal carcinoma cells. These results establish that tumor suppression by pVHL is linked to regulation of HIF target genes.

Subfields: Cancer Research, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/ffa0e8cb0116622e03216188d0844786ad447fc8

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

In Cancer Research

1. G. Semenza
2. M. C. Simon
3. W. Kaelin
4. P. Ratcliffe
5. Adrian L. Harris
6. Amato J. Giaccia
7. N. Denko
8. C. Pugh

In Molecular Biology

1. G. Semenza
2. M. C. Simon
3. W. Kaelin
4. P. Ratcliffe
5. Adrian L. Harris
6. M. Eddins
7. N. Denko
8. C. Pugh

Citations in the corpus

• Ubiquitin: structures, functions, mechanisms. (2004, background): “Members of the Hypoxia Inducible Factor (HIF) family of transcription factors are cancer-relevant substrates of the VCB E3 [126].”
• The von Hippel–Lindau tumour suppressor protein: O2 sensing and cancer (2008, background): “Moreover, short hairpin RNA-mediated downregulation of HIF2α is sufficient to promote cell-cycle exit of VHL −/− renal carcinoma cells under low serum conditions and suppresses tumour growth in vivo”
• HIF-1 mediates adaptation to hypoxia by actively downregulating mitochondrial oxygen consumption. (2006, background): “The ability to recognize modified HIF-as is at least partly responsible for VHL activity as a tumor suppressor, as introduction of nondegradable HIF-2a is capable of overcoming the growth–inhibitory activity of wild-type (wt) VHL in renal cancer cells (Kondo et al., 2003).”
• Contrasting Properties of Hypoxia-Inducible Factor 1 (HIF-1) and HIF-2 in von Hippel-Lindau-Associated Renal Cell Carcinoma (2005, methodology): “This process is disrupted by all RCC-associated VHL mutations tested to date (17), and overexpression of a HIF-2 gene that escapes VHLmediated destruction due to mutation of one or both prolyl hydroxylation sites blocks the tumor suppressor action of VHL in experimental tumors grown from transplante”
• The role of hypoxia-inducible factors in tumorigenesis (2008, background): “In VHL-deficient RCC cells, HIF-2 is both necessary and sufficient to maintain tumor growth.(71,72) Furthermore, tumors generated from RCC cell lines overexpressing HIF-2 grow at a faster rate compared to HIF-1-overexpressing tumors.”
• HIF-2alpha promotes hypoxic cell proliferation by enhancing c-myc transcriptional activity. (2007, background): “O RCC cells expressing pVHL restores xenograft growth to the level of parental VHL null cells (Kondo et al., 2002, 2003; Raval et al., 2005), whereas overexpression of stable HIF-1a inhibits tumor growth (Maranchie et al., 2002; Raval et al., 2005).”
• The N-Terminal Transactivation Domain Confers Target Gene Specificity of Hypoxia-inducible Factors HIF-1α and HIF-2α (2007, result): “These results are in agreement with functional studies indicating that HIF-1 and HIF-2 exhibit distinct roles during both development and tumor progression (Maranchie et al., 2002; Kondo et al., 2003; Scortegagna et al., 2003; Covello et al., 2005, 2006; Raval et al., 2005).”
• Therapeutic targeting of hypoxia and hypoxia-inducible factors in cancer. (2016, background): “Since HIF-2α rather than HIF-1α is the major driver of VHL-mutated ccRCC (Kondo et al., 2003; Carroll & Ashcroft, 2006), specific targeting of HIF-2 in this tumor is likely to be more beneficial.”