mTORC2 links growth factor signaling with epigenetic regulation of iron metabolism in glioblastoma.

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.

• Authors: Kenta Masui, Mio Harachi, Shiro Ikegami, Huijun Yang, Hiromi Onizuka, William H Yong, Timothy F Cloughesy, Yoshihiro Muragaki, Takakazu Kawamata, Nobutaka Arai, Takashi Komori, Webster K Cavenee, Paul S Mischel, Noriyuki Shibata
• Journal: The Journal of biological chemistry (J Biol Chem) Vol. 294 Issue 51 Pg. 19740-19751 (12 20 2019) ISSN: 1083-351X [Electronic] United States
• PMID: 31712311 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: © 2019 Masui et al.

Chemical References

• Histones
• Immediate-Early Proteins
• Intercellular Signaling Peptides and Proteins
• Iron
• Pyruvate Dehydrogenase (Lipoamide)
• AKT1 protein, human
• Mechanistic Target of Rapamycin Complex 2
• Protein Serine-Threonine Kinases
• Proto-Oncogene Proteins c-akt
• serum-glucocorticoid regulated kinase

Topics

• Active Transport, Cell Nucleus
• Animals
• Brain Neoplasms (metabolism)
• Cell Line, Tumor
• Cell Survival
• Epigenesis, Genetic
• Gene Expression Regulation, Neoplastic
• Glioblastoma (metabolism)
• Histones (chemistry)
• Humans
• Immediate-Early Proteins (metabolism)
• Intercellular Signaling Peptides and Proteins (metabolism)
• Iron (metabolism)
• Mechanistic Target of Rapamycin Complex 2 (metabolism)
• Metabolome
• Mice
• Neoplasm Transplantation
• Promoter Regions, Genetic
• Protein Serine-Threonine Kinases (metabolism)
• Proto-Oncogene Proteins c-akt (metabolism)
• Pyruvate Dehydrogenase (Lipoamide) (metabolism)
• Signal Transduction