# HDAC inhibitors reverse the Warburg Effect and Elicit Metabolic Vulnerabilities in Model Systems of Glioblastoma

> **NIH NIH R01** · COLUMBIA UNIVERSITY HEALTH SCIENCES · 2022 · $405,000

## Abstract

Glioblastoma multiforme (GBM) is the most common primary brain tumor with about
8500 cases diagnosed each year in the United States. Within a time frame of roughly
one year almost all patients succumb to this detrimental disease despite treatment.
Therefore, novel, ideally tumor specific approaches are necessary to combat these
tumors. Akin to other malignancies, GBMs depend on aerobic glycolysis, meaning that
paradoxically glucose is metabolized to lactate in the presence of an abundance of
molecular oxygen (Warburg-effect). Based on a chromatin immunoprecipitation
sequencing and transcriptome analysis, we found that HDAC-inhibition through
panobinostat, vorinostat and FK228 results in reprogramming of metabolism in stem-like
and established GBM cells, which is orchestrated in part by the modulation of three key
transcription factors. This leads to a significant reduction of glycolysis (reversal of the
Warburg effect) with lower overall ATP levels. HDAC treated GBM cells reactivate
oxidative phosphorylation (OXPHOS). Consistently, interference with mitochondrial
translation or ATP production enhanced apoptosis in stem-like glioma and patient
derived xenograft (PDX) cells. To fuel OXPHOS, HDAC treated glioblastoma cells
increased the levels of transporters and enzymes related to fatty acid oxidation (FAO)
and pharmacological inhibition of FAO by the clinically validated compound, Etomoxir,
synergistically induced apoptosis in PDX, stem-like and established glioblastoma cells in
vitro as well as in PDX models in vivo. Overall, this research will enhance our
understanding about the treatment of brain tumors and may potentially allow us to
formulate a novel treatment strategy for glioblastomas and other gliomas.

## Key facts

- **NIH application ID:** 10376222
- **Project number:** 5R01NS113793-02
- **Recipient organization:** COLUMBIA UNIVERSITY HEALTH SCIENCES
- **Principal Investigator:** MARKUS D SIEGELIN
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $405,000
- **Award type:** 5
- **Project period:** 2021-04-01 → 2026-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10376222

## Citation

> US National Institutes of Health, RePORTER application 10376222, HDAC inhibitors reverse the Warburg Effect and Elicit Metabolic Vulnerabilities in Model Systems of Glioblastoma (5R01NS113793-02). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10376222. Licensed CC0.

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