Editors' ChoiceCancer

Linking Aberrant Metabolism to Oncogenesis

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Sci. Signal.  27 Mar 2012:
Vol. 5, Issue 217, pp. ec97
DOI: 10.1126/scisignal.2003076

Malignant gliomas, like certain other human cancers, frequently carry mutations in isocitrate dehydrogenase 1 (IDH1) and IDH2, enabling these enzymes to produce the oncogenic metabolite 2-hydroxyglutarate (2HG). Three papers explore the relationship between IDH mutation and glioma, with two studies implicating mutant IDH in aberrant methylation and the third linking 2HG to degradation of the transcription factor HIF (hypoxia-inducible factor). IDH1 mutation is associated with the proneural subtype of glioma, which shows a CpG island methylator phenotype (CIMP, characterized by the coordinated hypermethylation of specific loci). Turcan et al. showed that introduction of mutant IDH1 into immortalized primary human astrocytes led to progressive remodeling of the methylome (followed over up to 50 successive passages) to reflect that of CIMP-positive lower-grade gliomas. After determining that the IDH mutation was associated with a gene expression profile enriched in genes expressed in neural progenitor cells, Lu et al. showed that mutant IDH1 or IDH2 increased histone methylation in 293T cells, with the magnitude of the increase correlating with the abundance of cellular 2HG. Mutant IDH blocked differentiation of 3T3-L1 cells into adipocytes, as did a cell-permeant form of 2HG, and increased repressive histone methylation. Human gliomas with mutant IDH1 showed increased repressive trimethylation of histone H3 lysine 9 (H3K9) compared to those with wild-type IDH1, and stable transfection of mutant IDH1 into immortalized human astrocytes led to a progressive increase in histone methylation with passage in culture that preceded increased methylation of DNA. Abundance of the H3K9-specific demethylase KDM4C, which was sensitive to inhibition by 2HG, increased during 3T3-L1 cell differentiation, and KDM4C knockdown both increased H3K9 trimethylation in 3T3-L1 cells and impaired their ability to differentiate. In the third study, Koivunen et al. showed that, with passage in culture, immortalized human astrocytes stably transfected with a tumor-associated mutant form of IDH1 developed a proliferative advantage, compared to cells transfected with wild-type IDH1 or a catalytically inactive mutant, and the ability to grow in soft agar. Mutant IDH1 specifically produces the (R)-enantiomer of 2HG [(R)-2HG], and, although both (R)- and (S)-2HG inhibited various enzymes, (R)-2HG stimulated the activity of EGLN HIF prolyl 4-hydroxylases (enzymes that mark HIF for proteolytic degradation), whereas (S)-2HG inhibited it. The abundance of HIF-1α and HIF-2α was decreased in midpassage astrocytes bearing mutant IDH1, as was the hypoxia-dependent increase in the abundance of HIF target mRNAs. HIF-1α knockdown promoted the growth in soft agar of immortalized human astrocytes, as did EGLN1 overexpression, whereas EGLN1 knockdown inhibited the proliferation of astrocytes expressing mutant IDH1. Thus, all three studies shed light on the mechanisms linking mutant IDH1 to gliomagenesis.

S. Turcan, D. Rohle, A. Goenka, L. A. Walsh, F. Fang, E. Yilmaz, C. Campos, A. W. M. Fabius, C. Lu, P. S. Ward, C. B. Thompson, A. Kaufman, O. Guryanova, R. Levine, A. Heguy, A. Viale, L. G. T. Morris, J. T. Huse, I. K. Mellinghoff, T. A. Chan, IDH1 mutation is sufficient to establish the glioma hypermethylator phenotype. Nature 483, 479–483 (2012). [PubMed]

C. Lu, P. S. Ward, G. S. Kapoor, D. Rohle, S. Turcan, O. Abdel-Wahab, C. R. Edwards, R. Khanin, M. E. Figueroa, A. Melnick, K. E. Wellen, D. M. O’Rourke, S. L. Berger, T. A. Chan, R. L. Levine, I. K. Mellinghoff, C. B. Thompson, IDH mutation impairs histone demethylation and results in a block to cell differentiation. Nature 483, 474–478 (2012). [PubMed]

P. Koivunen, S. Lee, C. G. Duncan, G. Lopez, G. Lu, S. Ramkissoon, J. A. Losman, P. Joensuu, U. Bergmann, S. Gross, J. Travins, S. Weiss, R. Looper, K. L. Ligon, R. G. W. Verhaak, H. Yan, W. G. Kaelin Jr., Transformation by the (R)-enantiomer of 2-hydroxyglutarate linked to EGLN activation. Nature 483, 484–488 (2012). [PubMed]

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