Abstract
Sterol regulatory element-binding protein-1a (SREBP1a) is a member of the SREBP family of transcription factors, which mainly controls homeostasis of lipids. SREBP1a can also activate the transcription of isocitrate dehydrogenase 1 (IDH1) by binding to its promoter region. IDH1 mutations, especially R132H mutation of IDH1, are a common feature of a major subset of human gliomas. There are few data available on the relationship between mutational IDH1 expression and SREBP1a pathway. In this study, we investigated cellular effects and SREBP1a pathway alterations caused by R132H mutational IDH1 expression in U87 cells. Two glioma cell lines, stably expressing mutational (U87/R132H) or wild type (U87/wt) IDH1, were established. A cell line, stably transfected with pcDNA3.1(+) (U87/vector), was generated as a control. Click-iT® EdU assay, sulforhodamine B assay, and wound healing assay respectively showed that the expression of R132H induced cellular proliferation, cell growth, and cell migration. Western blot revealed that SREBP1 was increased in U87/R132H compared with that in U87/wt. Elevated SREBP1a and several its target genes, but not SREBP1c, were detected by real-time polymerase chain reaction in U87/R132H. All these findings indicated that R132H mutational IDH1 is involved in the regulation of proliferation, growth, and migration of glioma cells. These effects may partially be mediated by SREBP1a pathway.
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Aghili M, Zahedi F, Rafiee E (2009) Hydroxyglutaric aciduria and malignant brain tumor: a case report and literature review. J Neurooncol 91(2):233–236
Balss J, Meyer J, Mueller W, Korshunov A, Hartmann C, von Deimling A (2008) Analysis of the IDH1 codon 132 mutation in brain tumors. Acta Neuropathol 116(6):597–602
Borodovsky A, Seltzer MJ, Riggins GJ (2012) Altered cancer cell metabolism in gliomas with mutant IDH1 or IDH2. Curr Opin Oncol 24(1):83–89
Brown MS, Goldstein JL (1997) The SREBP pathway: regulation of cholesterol metabolism by proteolysis of a membrane-bound transcription factor. Cell 89(3):331–340
Brown MS, Goldstein JL (1999) A proteolytic pathway that controls the cholesterol content of membranes, cells, and blood. Proc Natl Acad Sci USA 96(20):11041–11048
Chehrehasa F, Meedeniya AC, Dwyer P, Abrahamsen G, Mackay-Sim A (2009) EdU, a new thymidine analogue for labelling proliferating cells in the nervous system. J Neurosci Methods 177(1):122–130
Dang L, White DW, Gross S et al (2009) Cancer-associated IDH1 mutations produce 2-hydroxyglutarate. Nature 462(7274):739–744
Di Vizio D, Solomon KR, Freeman MR (2008) Cholesterol and cholesterol-rich membranes in prostate cancer: an update. Tumori 94(5):633–639
Edwards PA, Tabor D, Kast HR, Venkateswaran A (2000) Regulation of gene expression by SREBP and SCAP. Biochim Biophys Acta 1529(1–3):103–113
Fu Y, Huang R, Du J, Yang R, An N, Liang A (2010) Glioma-derived mutations in IDH: from mechanism to potential therapy. Biochem Biophys Res Commun 397(2):127–130
Gimpl G, Burger K, Fahrenholz F (2002) A closer look at the cholesterol sensor. Trends Biochem Sci 27(12):596–599
Guo D, Prins RM, Dang J et al (2009) EGFR signaling through an Akt-SREBP-1-dependent, rapamycin-resistant pathway sensitizes glioblastomas to antilipogenic therapy. Sci Signal 2(101):ra82
Hartmann C, Meyer J, Balss J et al (2009) Type and frequency of IDH1 and IDH2 mutations are related to astrocytic and oligodendroglial differentiation and age: a study of 1,010 diffuse gliomas. Acta Neuropathol 118(4):469–474
Horton JD, Goldstein JL, Brown MS (2002) SREBPs: activators of the complete program of cholesterol and fatty acid synthesis in the liver. J Clin Invest 109(9):1125–1131
Houillier C, Wang X, Kaloshi G et al (2010) IDH1 or IDH2 mutations predict longer survival and response to temozolomide in low-grade gliomas. Neurology 75(17):1560–1566
Kim YH, Nobusawa S, Mittelbronn M et al (2010) Molecular classification of low-grade diffuse gliomas. Am J Pathol 177(6):2708–2714
Louis DN, Ohgaki H, Wiestler OD et al (2007) The 2007 WHO classification of tumours of the central nervous system. Acta Neuropathologica 114(2):97–109
Parsons DW, Jones S, Zhang X et al (2008) An integrated genomic analysis of human glioblastoma multiforme. Science 321(5897):1807–1812
Pauwels B, Korst AE, de Pooter CM et al (2003) Comparison of the sulforhodamine B assay and the clonogenic assay for in vitro chemoradiation studies. Cancer Chemother Pharmacol 51(3):221–226
Reitman ZJ, Jin G, Karoly ED et al (2011) Profiling the effects of isocitrate dehydrogenase 1 and 2 mutations on the cellular metabolome. Proc Natl Acad Sci USA 108(8):3270–3275
Sanson M, Marie Y, Paris S et al (2009) Isocitrate dehydrogenase 1 codon 132 mutation is an important prognostic biomarker in gliomas. J Clin Oncol 27(25):4150–4154
Shechter I, Dai P, Huo L, Guan G (2003) IDH1 gene transcription is sterol regulated and activated by SREBP-1a and SREBP-2 in human hepatoma HepG2 cells: evidence that IDH1 may regulate lipogenesis in hepatic cells. J Lipid Res 44(11):2169–2180
SongTao Q, Lei Y, Si G et al (2012) IDH mutations predict longer survival and response to temozolomide in secondary glioblastoma. Cancer Sci 103(2):269–273
Sonoda Y, Kumabe T, Nakamura T et al (2009) Analysis of IDH1 and IDH2 mutations in Japanese glioma patients. Cancer Sci 100(10):1996–1998
Struys EA (2006) D-2-Hydroxyglutaric aciduria: unravelling the biochemical pathway and the genetic defect. J Inherit Metab Dis 29(1):21–29
Thon N, Eigenbrod S, Kreth S et al (2012) IDH1 mutations in grade II astrocytomas are associated with unfavorable progression-free survival and prolonged postrecurrence survival. Cancer 118(2):452–460
Vander Heiden MG, Cantley LC, Thompson CB (2009) Understanding the Warburg effect: the metabolic requirements of cell proliferation. Science 324(5930):1029–1033
Wen PY, Kesari S (2008) Malignant gliomas in adults. N Engl J Med 359(5):492–507
Yan H, Parsons DW, Jin G et al (2009) IDH1 and IDH2 mutations in gliomas. N Engl J Med 360(8):765–773
Yang YA, Morin PJ, Han WF et al (2003) Regulation of fatty acid synthase expression in breast cancer by sterol regulatory element binding protein-1c. Exp Cell Res 282(2):132–137
Zagzag D, Zhong H, Scalzitti JM, Laughner E, Simons JW, Semenza GL (2000) Expression of hypoxia-inducible factor 1alpha in brain tumors: association with angiogenesis, invasion, and progression. Cancer 88(11):2606–2618
Zhao S, Guan KL (2010) IDH1 mutant structures reveal a mechanism of dominant inhibition. Cell Res 20(12):1279–1281
Zhao S, Lin Y, Xu W et al (2009) Glioma-derived mutations in IDH1 dominantly inhibit IDH1 catalytic activity and induce HIF-1alpha. Science 324(5924):261–265
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This work was supported by Jiangsu Province’s Outstanding Medical Academic Leader program (no. LJ201139).
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Jian Zhu, Gang Cui, and Ming Chen equally contributed to this work.
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Zhu, J., Cui, G., Chen, M. et al. Expression of R132H Mutational IDH1 in Human U87 Glioblastoma Cells Affects the SREBP1a Pathway and Induces Cellular Proliferation. J Mol Neurosci 50, 165–171 (2013). https://doi.org/10.1007/s12031-012-9890-6
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DOI: https://doi.org/10.1007/s12031-012-9890-6