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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.

SUBMITTER: Masui K 

PROVIDER: S-EPMC6926466 | biostudies-literature | 2019 Dec

REPOSITORIES: biostudies-literature

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

Masui Kenta K   Harachi Mio M   Ikegami Shiro S   Yang Huijun H   Onizuka Hiromi H   Yong William H WH   Cloughesy Timothy F TF   Muragaki Yoshihiro Y   Kawamata Takakazu T   Arai Nobutaka N   Komori Takashi T   Cavenee Webster K WK   Mischel Paul S PS   Shibata Noriyuki N  

The Journal of biological chemistry 20191111 51


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 d  ...[more]

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