# Regulation of the Kidney Cancer Epigenome by Oncometabolite L-2-Hydroxyglutarate

> **NIH NIH R01** · UNIVERSITY OF ALABAMA AT BIRMINGHAM · 2020 · $338,596

## Abstract

PROJECT SUMMARY. Renal cell carcinoma (RCC) is among the 10 most common malignancies in both men
and women. Unfortunately, progress in the treatment of patients with advanced disease has been incremental,
and new treatment approaches are warranted. Altered metabolism, an established hallmark of malignancy,
may provide novel therapeutic opportunities. Oncometabolites, small molecules with putative transforming
properties, represent one of the clearest links between metabolism and cancer. A unifying theme amongst the
oncometabolites identified to date is their ability to alter the epigenome via inhibition of enzymes involved in
DNA and histone demethylation. In the context of RCC, there is increasing recognition of the role of
epigenetics to the pathogenesis of this malignancy. However, the drivers of the RCC epigenome remain
poorly characterized. The long-term goal of our laboratory is to understand the role of metabolism in renal
carcinogenesis to develop novel therapies that will improve outcomes. The objective of this proposal is to
identify the metabolic basis for the epigenetic landscape of RCC and to determine the effects on tumorigenesis.
Studies by our laboratory and others have identified elevations of the putative oncometabolite (L)-2-
hydroxyglutarate (L-2HG) in RCC as well as brain tumors. Elevations of L-2HG in RCC are due to reduced
expression of L2HGDH (L-2HG dehydrogenase) which is located on chromosome 14q. Intriguingly, 14q loss is
associated with a DNA hypermethylation phenotype, therapy resistance, and worsened outcomes in RCC
patients. The central hypothesis of this proposal is that L-2HG is a powerful epigenetic modifier that drives the
malignant phenotype of RCC. This hypothesis is based on strong preliminary data demonstrating that re-
expression of L2HGDH in RCC cells (and thus lowering of cellular L-2HG levels) can reverse epigenetic
modifications and suppresses both in vitro and in vivo tumor phenotypes. Additionally, high L-2HG tumors
from patients demonstrate a RCC hypermethylator phenotype. In Aim 1, we will dissect the genetic and
biochemical events that lead to L-2HG accumulation. In Aim 2, we will determine the contribution of L-2HG to
the hypermethylator phenotype and assess the effects on gene expression utilizing methodologies including
next generation sequencing with methylome array. In Aim 3, we will determine the mechanism by which
L2HGDH suppresses tumor growth. In addition, we will assess the role of L2HGDH loss in tumor initiation and
progression using novel genetic models. The proposed research is significant because it will identify the
drivers of the RCC epigenome in the context of targetable pathways. The approach is innovative because it
will establish a link between the epigenome and tumor metabolism in RCC. Ultimately, the knowledge
gathered has the potential to improve the efficacy of treatment for patients with advanced RCC, an unmet need
challenging the contemporary management of this disease.

## Key facts

- **NIH application ID:** 9962889
- **Project number:** 5R01CA200653-05
- **Recipient organization:** UNIVERSITY OF ALABAMA AT BIRMINGHAM
- **Principal Investigator:** SUNIL SUDARSHAN
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $338,596
- **Award type:** 5
- **Project period:** 2016-07-01 → 2022-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9962889

## Citation

> US National Institutes of Health, RePORTER application 9962889, Regulation of the Kidney Cancer Epigenome by Oncometabolite L-2-Hydroxyglutarate (5R01CA200653-05). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9962889. Licensed CC0.

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