# HDAC7-driven metabolic remodeling in renal tumor progression

> **NIH VA I01** · BIRMINGHAM VA MEDICAL CENTER · 2023 · —

## Abstract

Renal cell carcinoma (RCC) is among the 10 most common malignancies in both men and women. It is also a
malignancy that is prevalent in the Veteran population. An analysis of VA Central Cancer Registry (VACCR)
data demonstrates that cancer of the kidney is among the most common cancers in the veteran population. The
most common histology is clear cell RCC (ccRCC), the focus of this proposal. One-third of patients will develop
metastasis. Unfortunately, most patients who develop metastasis will die from their disease. These realities
have created two fundamental gaps: 1) what are the mechanisms that mediate aggressive behavior in RCC?
and 2) can we target these mechanisms? The goals of this proposal will be to address these major gaps in the
field to improve outcome for Veterans, as well as the greater population afflicted with RCC. The kidney is among
the most metabolically active organs in the human body. Notably, RCC harbors dramatic alterations in metabolic
gene expression programs. The most well-studied metabolic pathway in RCC is glycolysis as the expression
of enzymes that mediate this pathway are upregulated due increased expression of hypoxia inducible factor
(HIF). However, an equally compelling phenotype is our data demonstrating dramatically reduced expression of
enzymes that mediate the catabolism (i.e., breakdown) of branched chain amino acids (BCAAs). BCAAs are
essential amino acids, and therefore must be obtained from the diet. BCAA catabolism occurs in the
mitochondria and consists of a complex series of reactions that mediate the breakdown of valine, leucine, and
isoleucine. Amongst all tumor types, loss of the BCAA catabolism program is most strongly associated with
death for patients with kidney cancer. Despite this compelling link, the mechanisms that drive this remodeling
and its impact on tumor biology are poorly understood. The objective of this proposal is to identify the key drivers
of metabolic remodeling and the molecular underpinnings by which this remodeling propels tumor progression.
Elucidating this molecular connection will yield novel strategies to counter tumor progression which would
improve patient outcomes. Our preliminary data uncover a novel role for the epigenetic factor histone
deacetylase 7 (HDAC7) in suppressing the BCAA catabolic gene expression program in RCC. Our data indicate
this reroutes BCAAs toward protumorigenic pathways based on our findings demonstrating that HDAC7 inhibition
restores expression of BCAA catabolism enzymes and suppresses tumor growth in vivo. In turn, our data
uncover a novel role for BCAAs in the activation of signaling nodes that promote aggressive behaviors in cancer
cells. These data have led us to propose the novel hypothesis that HDAC7 reprogramming of BCAA metabolism
drives RCC progression This central hypothesis, based on strong preliminary data, will be tested through pursuit
of the following specific aims: 1) determine the epigenetic basis by which BCAA catabolism is ...

## Key facts

- **NIH application ID:** 10587999
- **Project number:** 2I01BX002930-09
- **Recipient organization:** BIRMINGHAM VA MEDICAL CENTER
- **Principal Investigator:** SUNIL SUDARSHAN
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2023
- **Award amount:** —
- **Award type:** 2
- **Project period:** 2015-04-01 → 2027-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10587999

## Citation

> US National Institutes of Health, RePORTER application 10587999, HDAC7-driven metabolic remodeling in renal tumor progression (2I01BX002930-09). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10587999. Licensed CC0.

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