Oncotarget Investigation of the role of VHL-HIF signaling in DNA repair and apoptosis


Oncotarget Volume 11, Issue 13 reported that although HIF promotes the progression of cc RCC, the precise mechanism by which the loss of VHL leads to tumor initiation remains unclear.

This research team exploited two zebrafish vhl mutants, vhl and vll, and Tg i144 fish to identify crucial functions of Vhl in tumor initiation.

Dr. Fredericus J. van Eeden from the Bateson Centre/BMS, Firth Court, University of Sheffield, Sheffield S10 2TN, UK said "In humans, mutations in the pVHL protein, a tumor suppressor protein, predispose patients to Von Hippel Lindau (VHL) disease, a rare form of dominantly inherited cancer syndrome."

"In humans, mutations in the pVHL protein, a tumor suppressor protein, predispose patients to Von Hippel Lindau (VHL) disease, a rare form of dominantly inherited cancer syndrome."

- Dr. Fredericus J. van Eede, Bateson Centre/BMS, Firth Court, University of Sheffield

In contrast to earlier studies with cc RCC cell lines and tumor xenograft studies which suggested the role of HIF1 as a tumor suppressor, more recent mouse transgenic model with constitutive activation of HIF1 demonstrated the role of HIF1 in the early cc RCC lesion formation, such as renal cyst and clear cell morphology.

Demonstrating that pVHL is required for DSB repair in cc RCC cell lines, implicating the role of pVHL in DNA damage repair as a cause of the genomic instability in cc RCC.

It was speculated that the downregulation of DNA repair genes in cc RCC cell lines is due to the activation of HIF2 rather than HIF1, since cc RCC cells expressing only HIF2 exhibit the same gene expression profile as that of the cells expressing both HIF transcription factors, i. e. downregulated DNA repair genes.

Figure 1: A  vll mutant allele,  vll<sup>216</sup>, is generated by a zinc finger nuclease.

Figure 1: A vll mutant allele, vll216, is generated by a zinc finger nuclease. (A) The mutant allele harbors 23 nucleotide deletion around translational starting site. (B) Zebrafish Vll shares 52% homology with human VHL. The seven amino acids that are lost in vll216 are highlighted in red. Even if the next available ATG (highlighted in blue) were to be used as an alternative translational start site, it would lead to a protein that lacks most of the predicted Hif binding domain. (C) Since phd3 (egln3) expression most dramatically reflects the increased Hif expression, we used Tg (phd3:: EGFP)i144 transgenic line as a Hif signaling readout. Zebrafish vll–/– embryos do not show any morphological phenotype and the Tg (phd3:: EGFP)i144 expression in the mutants was identical to that in the wild type embryos. Reflecting the role of Vll in Hif regulation in the absence of Vhl, there was an enhanced GFP expression in the vhl–/–; vll–/– double mutant embryos in comparison to that in vhl–/– embryos. Scale bar: 1 mm.

More importantly, cc RCC is notorious for its resistance to chemotherapeutic reagents; therefore, it can be speculated that if there is a defect in the DNA repair in the cc RCC as the above two papers suggest, the tumor cells will be extremely sensitive to, rather than resistant to, the DNA damaging reagents further emphasizing the limits of cell lines for studies.

Interestingly the function of human VHL in HIF regulation and DNA repair seems to be partially segregated into zebrafish Vhl and Vll respectively, Hif regulation in Vhl and DNA repair in Vll.

The van Eeden Research Team concluded in their Oncotarget Research Paper, "we discovered that HIF regulation and DNA repair role of human VHL are conserved in zebrafish vhl and vll. The activated Hif in the vhl; vll mutants strongly suppresses DNA damage and apoptosis induced by genotoxic stress. We speculate this could parallel resistance to chemo- and radio therapies in ccRCC, and propose zebrafish vhl–/–; vll–/– double mutants as a powerful model for the development of therapeutic reagents to overcome the resistance of ccRCC to chemo- and radio therapies. We found Hif activation suppresses the DNA damage in the brca2 and vll mutants and ATM deficient embryos and also prevents apoptosis. Currently at least one HIF activator is in the phase III clinical trials for the treatment of anemia [52, 53]. Our results suggest that clinical benefits of HIF activation could expand beyond treatment of anemia, to that of disorders linked with DNA repair deficiency, like Ataxia Telangiectasia."

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DOI - https://doi.org/10.18632/oncotarget.27521

Full text - https://www.oncotarget.com/article/27521/text/

Correspondence to - Fredericus J. van Eeden - [email protected]

Keywords - Hif, Vhl, DNA repair, apoptosis, chemo/radio-resistance

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