# New Von Hippel Lindau (VHL) tumor suppressor signaling in renal cancer

> **NIH NIH R01** · UT SOUTHWESTERN MEDICAL CENTER · 2024 · $546,349

## Abstract

Project Summary
Clear cell renal cell carcinoma (ccRCC), which accounts for approximately 85% of all renal cancers, is resistant
to a variety of cancer therapies and is highly lethal. von Hippel-Lindau (VHL) is the most important tumor
suppressor in renal cancer, its loss leads to hypoxia inducible factor  (HIF, including HIF1α and HIF2α)
accumulation. Although HIF2α inhibitor has been developed as a potential therapeutic target in renal cancer,
only a small propotion of patients will respond to HIF2α inhibitore treatment, suggesting the importance of
identifying additional therapeutic vulnerabilities in VHL-deficient kidney cancer. Methylation of adenosine (m6A)
determines the fate of modified messenger RNAs (mRNAs) and has recently been shown to play a key role
regulating gen expression critical in cancer development. Although previous research has suggested that m6A
may be important in renal cancer, the molecular mechanism behind its role in ccRCC tumorigenesis and
aggression is not yet well understood. Our preliminary data suggest that VHL binds to m6A enzymatic complex
proteins Mettl3/14 and regulates their interaction. By performing m6A RIP-Seq and RNA-Seq in renal cells with
and without VHL, we have identified a set of genes whose expression may be regulated by m6A in a VHL-
dependent manner. Among them, Phosphoinositide-3-Kinase Regulatory Subunit 3 (PIK3R3), an important
component of PI3K pathway, its mRNA stability is regulated by VHL in an m6A-dependent manner. Functionally,
PIK3R3 depletion promotes renal cell growth and tumor growth while its overexpression diminishes ccRCC cell
growth on 2-D colony formation, 3-D soft agar growth and tumor growth. We hypothesize that VHL regulates
m6A-dependent gene expression, thereby controlling ccRCC tumorigenesis. This is the first study to link
VHL with mRNA stability regulation via regulating the Mettl3/14 m6A enzymatic complex, which characterizes
the noncanonical function of VHL distinctive from its role as an E3 ubiquitin ligase. In Specific Aim 1, we will
determine the molecular mechanism by which VHL regulates m6A modification in kidney cancer. In Specific Aim
2, we will examine the functional role of VHL-m6A signaling in ccRCC tumorigenesis. Specifically, we will
examine the therapeutic efficacy or PI3K and AKT inhibitors in kidney cancer xenografts and patient derived
xenografts. Successful completion of these aims will provide mechanistic insight into a novel signaling pathway
on how VHL regulates gene expression important in ccRCC and set the foundation for therapeutic intervention
targeting the VHL-Mettl3/14-m6A signaling axis in ccRCC.

## Key facts

- **NIH application ID:** 10997272
- **Project number:** 1R01CA294636-01
- **Recipient organization:** UT SOUTHWESTERN MEDICAL CENTER
- **Principal Investigator:** Qing Zhang
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $546,349
- **Award type:** 1
- **Project period:** 2024-08-07 → 2029-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10997272

## Citation

> US National Institutes of Health, RePORTER application 10997272, New Von Hippel Lindau (VHL) tumor suppressor signaling in renal cancer (1R01CA294636-01). Retrieved via AI Analytics 2026-06-12 from https://api.ai-analytics.org/grant/nih/10997272. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*