SREBP maintains lipid biosynthesis and viability of cancer cells under lipid- and oxygen-deprived conditions and defines a gene signature associated with poor survival in glioblastoma multiforme

Lewis, Caroline A.; Brault, C.; Peck, Barrie; Bensaad, Karim; Griffiths, Beatrice; Mitter, Richard; Chakravarty, Probir; East, Philip; Dankworth, Beatrice; Alibhai, Dominic; Harris, Adrian L.; Schulze, Almut

doi:10.1038/onc.2014.439

Cited by 197 publications

(166 citation statements)

References 67 publications

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“…Increased SREBP-1 activity and de novo lipid synthesis is a critical feature of a prostate cancer metabolic program that depends on activated steroid receptor coactivator 2 [86]. Moreover, inhibition of SREBPs attenuated the growth of glioblastoma cell xenografts [87] and SREBPs defined a gene signature associated with poor survival in glioblastoma [88]. Thus, SREBP inhibition may become a new treatment strategy for some cancers and complementary efforts in oncology and metabolism may advance the design and development of new SREBP inhibitors.…”

Section: Bf175mentioning

confidence: 97%

Targeting SREBPs for treatment of the metabolic syndrome

Soyal

Nofziger

Dossena

et al. 2015

Trends in Pharmacological Sciences

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Section: Bf175mentioning

confidence: 97%

Targeting SREBPs for treatment of the metabolic syndrome

Soyal

Nofziger

Dossena

et al. 2015

Trends in Pharmacological Sciences

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“…The SREBP transcription factors have emerged as major drivers of lipid synthesis in the liver and in cancer (3,8,44,45). Since de novo lipogenesis consumes large quantities of carbon and reducing power in the form of NADPH, cells must adapt their metabolism to provide the necessary substrates.…”

Section: Discussionmentioning

confidence: 99%

Sterol Regulatory Element Binding Protein Regulates the Expression and Metabolic Functions of Wild-Type and Oncogenic IDH1

Ricoult

Dibble

Asara

et al. 2016

Molecular and Cellular Biology

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bSterol regulatory element binding protein (SREBP) is a major transcriptional regulator of the enzymes underlying de novo lipid synthesis. However, little is known about the SREBP-mediated control of processes that indirectly support lipogenesis, for instance, by supplying reducing power in the form of NAPDH or directing carbon flux into lipid precursors. Here, we characterize isocitrate dehydrogenase 1 (IDH1) as a transcriptional target of SREBP across a spectrum of cancer cell lines and human cancers. IDH1 promotes the synthesis of lipids specifically from glutamine-derived carbons. Neomorphic mutations in IDH1 occur frequently in certain cancers, leading to the production of the oncometabolite 2-hydroxyglutarate (2-HG). We found that SREBP induces the expression of oncogenic IDH1 and influences 2-HG production from glucose. Treatment of cells with 25-hydroxycholesterol or statins, which respectively inhibit or activate SREBP, further supports SREBP-mediated regulation of IDH1 and, in cells with oncogenic IDH1, carbon flux into 2-HG. The sterol regulatory element (SRE) binding protein (SREBP) family of transcription factors is activated by sterol depletion, growth factor signaling pathways, and oncogenes to induce the expression of genes encoding the major enzymes of de novo lipid synthesis (1-5). In sterol-replete conditions, inactive SREBP is held in the endoplasmic reticulum (ER). Upon sterol depletion, SREBP traffics from the ER to the Golgi apparatus, where it is proteolytically processed, leading to the release of a mature, active SREBP transcription factor (6, 7). The mature SREBP then translocates to the nucleus and binds SRE-containing gene promoters to induce transcription. The three SREBP isoforms are produced from two different genes: SREBF1, which encodes SREBP1a and SREBP1c, and SREBF2, which encodes SREBP2. Although studies of isoform-specific functions of the SREBPs in the liver have pointed to a role for SREBP1c in fatty acid and triglyceride synthesis and SREBP2 in cholesterol synthesis (8), SREBP targets appear to be more redundantly regulated in other settings (see, for example, references 3 and 4).The transcriptional activation of de novo lipid synthesis genes by SREBP is well studied, but less is known about the regulation of auxiliary genes that indirectly support lipogenesis by providing NADPH or directing carbon flux into lipids (8). Overexpression of mature, active SREBP in the liver of mice increases the transcription of genes encoding glucose-6-phosphate dehydrogenase, 6-phosphogluconate dehydrogenase, and malic enzyme 1, which are all major sources of NADPH production (9, 10). Similarly, mature SREBP increases the expression of acetyl coenzyme A (acetyl-CoA) synthetase (ACSS2) and ATP-citrate lyase (ACLY), as well as the mitochondrial citrate transporter (SLC25A1), which facilitate the flux of carbons into lipids from acetate and citrate, respectively (11-14). Isocitrate dehydrogenase 1 (IDH1) is another enzyme that can support lipogenesis either through NADPH production or, throug...

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“…HIG2 is a potential diagnostic marker for renal cell carcinoma and a promising target for molecular therapy [14]. HIG2 potentiated WNT pathway and lipid metabolism activation [14], both of which are important for glioma tumorigenesis [15, 16]. In addition, HIG2 can promote tumor cell growth by inhibiting apoptosis [13].…”

Section: Introductionmentioning

confidence: 99%

Hypoxia upregulates HIG2 expression and contributes to bevacizumab resistance in glioblastoma

et al. 2016

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Hypoxia contributes to the maintenance of stem-like cells in glioblastoma (GBM), and activates vascular mimicry and tumor resistance to anti-angiogenesis treatments. The present study examined the expression patterns and biological significance of hypoxia-inducible protein 2 (HIG2, also known as HILPDA) in GBM. HIG2 was highly expressed in gliomas and was correlated with tumor grade, and high HIG2 expression independently predicted poor GBM patient prognosis. HIG2 was upregulated during hypoxia and by hypoxia mimics, and HIG2 knockdown in GBM cells inhibited cell proliferation and invasion. HIF1α bound to the HIG2 promoter and increased its expression in GBM cells, and HIG2 upregulated HIF1α expression. Reconstruction of a HIG2-related molecular network using bioinformatics methods revealed that HIG2 is closely correlated with angiogenesis genes, such as VEGFA, in GBM. HIG2 levels positively correlated with VEGFA in GBM samples. In addition, treatment of transplanted xenograft nude mice with bevacizumab (anti-angiogenesis therapy) resulted in HIG2 upregulation at late stages. We conclude that HIG2 is overexpressed in GBM and upregulated by hypoxia, and is a potential novel therapeutic target. HIG2 overexpression is an independent prognostic indicator and may promote tumor resistance to anti-angiogenesis treatments.

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SREBP maintains lipid biosynthesis and viability of cancer cells under lipid- and oxygen-deprived conditions and defines a gene signature associated with poor survival in glioblastoma multiforme

Cited by 197 publications

References 67 publications

Targeting SREBPs for treatment of the metabolic syndrome

Targeting SREBPs for treatment of the metabolic syndrome

Sterol Regulatory Element Binding Protein Regulates the Expression and Metabolic Functions of Wild-Type and Oncogenic IDH1

Hypoxia upregulates HIG2 expression and contributes to bevacizumab resistance in glioblastoma

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