The oncometabolite 2-hydroxyglutarate activates the mTOR signalling pathway

Abstract

The identification of cancer-associated mutations in the tricarboxylic acid (TCA) cycle enzymes isocitrate dehydrogenases 1 and 2 (IDH1/2) highlights the prevailing notion that aberrant metabolic function can contribute to carcinogenesis. IDH1/2 normally catalyse the oxidative decarboxylation of isocitrate into α-ketoglutarate (αKG). In gliomas and acute myeloid leukaemias, IDH1/2 mutations confer gain-of-function leading to production of the oncometabolite R-2-hydroxyglutarate (2HG) from αKG. Here we show that generation of 2HG by mutated IDH1/2 leads to the activation of mTOR by inhibiting KDM4A, an αKG-dependent enzyme of the Jumonji family of lysine demethylases. Furthermore, KDM4A associates with the DEP domain-containing mTOR-interacting protein (DEPTOR), a negative regulator of mTORC1/2. Depletion of KDM4A decreases DEPTOR protein stability. Our results provide an additional molecular mechanism for the oncogenic activity of mutant IDH1/2 by revealing an unprecedented link between TCA cycle defects and positive modulation of mTOR function downstream of the canonical PI3K/AKT/TSC1-2 pathway.

Nuclear mTOR acts as a transcriptional integrator of the androgen signaling pathway in prostate cancer

“…However, the role, if any, that these classic mTOR partners play in transcriptional regulation remains to be determined. Interestingly, it was shown recently that DEPTOR can interact with KDM4A, a histone demethylase enzyme that contributes to the epigenetic regulation of the genome (Carbonneau et al 2016). In that context, blockade of mTOR-either mTORC1 (rapamycin) or both mTORC1/2 (torin 1)-would be predicted to impair gene transcriptional regulation with potentially stronger effects from dual-complex inhibition, as observed in the present study with torin 1.…”

A Pan-Cancer Proteogenomic Atlas of PI3K/AKT/mTOR Pathway Alterations

“…These mutations and proteins would suggest a model (Figure 7E), whereby mutant IDH1 may lead to high phospho-ERK (Chaturvedi et al, 2013), and SRC can activate PI3K (Chen et al, 2015; Su et al, 2016) and where activated mTOR signaling may activate transcription targets of hypoxia via HIF-1alpha (particularly in the absence of VHL), including NDRG1 and growth factors that may lead to a further increase ERK and PI3K signaling (Clark, 2009). Notably, VHL was recently found to directly suppress AKT activity (Guo et al, 2016), and generation of 2-hydroxyglutarate (2HG) by mutated IDH1/2 was also recently found to lead to the activation of mTOR (Carbonneau et al, 2016); our data here would highlight the importance of both of the above relationships in the setting of human cancer.…”

“…(D) Top differentially expressed proteins in HIGH P-AKT group compared to unaligned and PI3K-altered groups (see Methods), not including core PI3K/AKT/mTOR members. (E) Diagram of interactions involving PI3K/AKT/MTOR pathway represented by selected features from (C) and (D) (Carbonneau et al, 2016; Dodd et al, 2015; Guo et al, 2016; Weiler et al, 2014), with differential protein expression patterns represented, comparing tumors in HIGH P-AKT group with tumors harboring PI3K/RTK genomic alteration or with unaligned tumors. P values by t-test on log-transformed data.…”

Glutamine-derived 2-hydroxyglutarate is associated with disease progression in plasma cell malignancies

“…Furthermore, the ex vivo assessment of glutamine uptake by clonal PCs in comparison with the remainder of the BM mononuclear cells in patients with MM included in our study confirms the increased glutamine anaplerosis in clonal PCs ( Figure 5). 2-HG is a known oncometabolite derived from α-ketoglutarate and is associated with epigenetic modifications, as well activation of the mTOR signaling pathway (20), causing tumorigenesis in various cancers, especially those associated with IDH1/2 mutations such as acute myeloid leukemia (11,12) and glioblastoma (13,21). However, in certain subtypes of breast cancer, 2-HG was also found to be produced from α-ketoglutarate as a result of glutamine anaplerosis into the TCA cycle driven by c-MYC overexpression in the absence of IDH1/2 mutations (14).…”