| Title: |
ETMM-05. LACTIC ACID FACILITATES GLIOBLASTOMA GROWTH THROUGH MODULATION OF THE EPIGENOME |
| Authors: |
Torrini, Consuelo; Nguyen, Trang; Shu, Chang; Mela, Angeliki; Humala, Nelson; Mahajan, Aayushi; Karpel-Massler, Georg; Bruce, Jeffrey; Canoll, Peter; Siegelin, Markus |
| Source: |
Neuro-Oncology Advances ; volume 3, issue Supplement_1, page i15-i15 ; ISSN 2632-2498 |
| Publisher Information: |
Oxford University Press (OUP) |
| Publication Year: |
2021 |
| Description: |
Glioblastoma (GBM) is the most common primary malignant brain tumor with an unfavorable prognosis. While GBMs utilize glucose, there are other carbon sources at their disposal. Lactate accumulates to a significant amount in the infiltrative margin of GBMs. In the current study, we demonstrated that lactate rescued patient-derived xenograft (PDX) GBM cells from nutrient deprivation mediated cell death and inhibition of growth. Transcriptome analysis, ATAC-seq and CHIP-seq. showed that lactic acid exposure entertained a signature of cell cycle progression and oxidative phosphorylation (OXPHOS) /tricarboxylic acid (TCA)-cycle. LC/MS analysis demonstrated that U-13C-Lactate elicited substantial labeling of TCA-cycle metabolites, acetyl-CoA and histone protein acetyl-residues in PDX derived GBM cells. Given that acetyl-CoA is pivotal for histone acetylation we observed a dose-dependent elevation of histone marks (e.g. H3K27ac), which was rescued by genetic and pharmacological inhibition of lactic acid-uptake, ATP-citrate lyase, p300 histone-acetyl-transferase and OXPHOS, resulting in reversal of lactate mediated protection from cell death. CHIP-seq. analysis demonstrated that lactic acid facilitated enhanced binding of H3K27ac to gene promoters and cis-regulatory elements. Consistently, ATAC-seq. analysis highlighted enhanced accessibility of the chromatin by lactic acid. In a combined tracer experiment (U-13C-glucose and 3-C13-lactate), we made the fundamental observation that lactic acid carbons were predominantly labeling the TCA cycle metabolites over glucose, implying a critical role of lactic acid in GBMs. Finally, pharmacological blockage of the TCA-cycle, using a clinically validated drug, extended overall survival in an orthotopic PDX model in mice without induction of toxicity, implying a critical role of lactic acid in GBMs and establishing lactic acid metabolism as a novel drug target for GBM. |
| Document Type: |
article in journal/newspaper |
| Language: |
English |
| DOI: |
10.1093/noajnl/vdab024.061 |
| Availability: |
https://doi.org/10.1093/noajnl/vdab024.061; http://academic.oup.com/noa/article-pdf/3/Supplement_1/i15/36733776/vdab024.061.pdf |
| Rights: |
http://creativecommons.org/licenses/by-nc/4.0/ |
| Accession Number: |
edsbas.B9E00EB0 |
| Database: |
BASE |