Abstract
In cancer, aberrant growth factor receptor signaling reprograms cellular metabolism and global gene transcription to drive aggressive growth, but the underlying mechanisms are not well-understood. Here we show that in the highly lethal brain tumor glioblastoma (GBM), mTOR complex 2 (mTORC2), a critical core component of the growth factor signaling system, couples acetyl-CoA production with nuclear translocation of histone-modifying enzymes including pyruvate dehydrogenase and class IIa histone deacetylases to globally alter histone acetylation. Integrated analyses in orthotopic mouse models and in clinical GBM samples reveal that mTORC2 controls iron metabolisms via histone H3 acetylation of the iron-related gene promoter, promoting tumor cell survival. These results nominate mTORC2 as a critical epigenetic regulator of iron metabolism in cancer.
Highlights
In cancer, aberrant growth factor receptor signaling reprograms cellular metabolism and global gene transcription to drive aggressive growth, but the underlying mechanisms are not well-understood
Having shown that histone acetylation is dynamically controlled by mTOR complex 2 (mTORC2) through metabolic reprogramming, we examined its epigenetic effect on the expression of tumorpromoting genes because histone acetylation is generally considered to relax the chromatin configuration and facilitate the gene transcription [23, 24]
We have found that mTORC2 promotes GBM growth by altering iron metabolism, and we demonstrate that this activity is mediated by promoter histone modification
Summary
To examine the histone acetylation status in human GBM, we performed quantitative immunohistochemical analyses of EGFR/mTORC2 signaling, glycolytic enzyme lactate dehydrogenase A (LDHA) expression, and acetylation of histone H3 transferase; HDAC, histone deacetylase; TSA, tricostatin A; TSS, transcription start site; TFR, transferrin receptor; FTL, ferritin light chain; FTH1, ferritin heavy chain 1; FAC, ferric ammonium citrate; GAPDH, glyceraldehyde3-phosphate dehydrogenase
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