SIRT3-Mediated Dimerization of IDH2 Directs Cancer Cell Metabolism and Tumor Growth

Zou, Xianghui; Zhu, Yueming; Park, Seong Hoon; Liu, Guoxiang; O'Brien, Joseph; Jiang, Haiyan; Gius, David

doi:10.1158/0008-5472.can-16-2393

Cited by 73 publications

(46 citation statements)

References 36 publications

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“…Several other metabolic enzymes are known SIRT3 targets. For example, activation of IDH2 by SIRT3-dependent deacetylation can shift metabolism from glycolysis to oxidative phosphorylation [39], and the presence of IDH1 and IDH2 is important for survival of anchorage-independent cells by aiding in regeneration of NADPH for glutathione reduction [28]. Moreover, SIRT3 is a known activator of pyruvate dehydrogenase (PDH), resulting in enhance shuttling of pyruvate into the TCA cycle [40, 41].…”

Section: Discussionmentioning

confidence: 99%

Context-dependent activation of SIRT3 is necessary for anchorage-independent survival and metastasis of ovarian cancer cells

Kim

Gupta-Vallur

Jones

et al. 2019

Preprint

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Cells must alter their antioxidant capacity for maximal metastatic potential. However, the antioxidant adaptations required for transcoelomic metastasis, which is the passive dissemination of cancer cells in the peritoneal cavity as seen in ovarian cancer, have largely remained unexplored. Contradicting the need for oxidant scavenging by tumor cells is the observation that expression of the nutrient stress sensor and regulator of mitochondrial antioxidant defenses, SIRT3, is suppressed in many primary tumors. We discovered that this mitochondrial deacetylase is however, upregulated in a context-dependent manner in cancer cells. SIRT3 activity and expression transiently increased following ovarian cancer cell detachment and in tumor cells derived from malignant ascites of high-grade serous adenocarcinoma patients. Mechanistically, SIRT3 prevents mitochondrial superoxide surges in detached cells by regulating the manganese superoxide dismutase SOD2. This mitochondrial stress response is under dual regulation by SIRT3. SIRT3 rapidly increases SOD2 activity as an early adaptation to cellular detachment, which is followed by SIRT3-dependent transcriptional increases in SOD2 during sustained anchorage-independence. In addition, SIRT3 inhibits glycolytic capacity in anchorage-independent cells thereby contributing to metabolic changes in response to detachment. While manipulation of SIRT3 expression has few deleterious effects on cancer cells in attached conditions, SIRT3 up-regulation and SIRT3-mediated oxidant scavenging following matrix detachment are required for anoikis resistance in vitro, and both SIRT3 and SOD2 are necessary for colonization of the peritoneal cavity in vivo. Our results highlight the novel context-specific, pro-metastatic role of SIRT3 in ovarian cancer.

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Section: Discussionmentioning

confidence: 99%

Context-dependent activation of SIRT3 is necessary for anchorage-independent survival and metastasis of ovarian cancer cells

Kim

Gupta-Vallur

Jones

et al. 2019

Preprint

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“…The deacetylation of IDH2 prevents the oxidated state of the mitochondrial matrix milieu and helps to maintain the mitochondrial glutathione levels. Moreover, IDH2 acetylation was associated with a disturbance of the homodimeric IDH2 structure (200). Thus, the IDH2 K413Q mutant, simulating acetylation in the sense of the positive charge vanishing, also exhibited a reduced dimerization (200).…”

Section: Fig 3 Consequences Of Idh1/2-related Cancer Metabolism Formentioning

confidence: 97%

2-Hydroxyglutarate in Cancer Cells

Ježek

2020

Antioxidants & Redox Signaling

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Significance: Cancer cells are stabilized in an undifferentiated state similar to stem cells. This leads to profound modifications of their metabolism, which further modifies their genetics and epigenetics as malignancy progresses. Specific metabolites and enzymes may serve as clinical markers of cancer progression. Recent Advances: Both 2-hydroxyglutarate (2HG) enantiomers are associated with reprogrammed metabolism, in grade III/IV glioma, glioblastoma, and acute myeloid leukemia cells, and numerous other cancer types, while acting also in the cross talk of tumors with immune cells. 2HG contributes to specific alternations in cancer metabolism and developed oxidative stress, while also inducing decisions on the differentiation of naive T lymphocytes, and serves as a signal messenger in immune cells. Moreover, 2HG inhibits chromatin-modifying enzymes, namely 2-oxoglutarate-dependent dioxygenases, and interferes with hypoxia-inducible factor (HIF) transcriptome reprogramming and mammalian target of rapamycin (mTOR) pathway, thus dysregulating gene expression and further promoting cancerogenesis. Critical Issues: Typically, heterozygous mutations within the active sites of isocitrate dehydrogenase isoform 1 (IDH1) R132H and mitochondrial isocitrate dehydrogenase isoform 2 (IDH2) R140Q provide cells with millimolar r-2-hydroxyglutarate (r-2HG) concentrations, whereas side activities of lactate and malate dehydrogenase form submillimolar s-2-hydroxyglutarate (s-2HG). However, even wild-type IDH1 and IDH2, notably under shifts toward reductive carboxylation glutaminolysis or changes in other enzymes, lead to ''intermediate'' 0.01-0.1 mM 2HG levels, for example, in breast carcinoma compared with 10-8 M in noncancer cells. Future Directions: Uncovering further molecular metabolism details specific for given cancer cell types and sequence-specific epigenetic alternations will lead to the design of diagnostic approaches, not only for predicting patients' prognosis or uncovering metastases and tumor remissions but also for early diagnostics. Antioxid. Redox Signal. 00, 000-000.

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“…Specifically, IDH2 activity is sensitive to acetylation (22,27). The deacetylation of K413, in fact, increases IDH2 activity, whereas the constitutive acetylation mimic mutant, K256 to glutamine (K256 → Q), reduces it (22,27,47). Although proteomic analyses and site-specific mutagenesis indicated the presence of additional putatively acetylated lysines (27,48), no information is currently available about their functional role, and no evidence has been provided so far about the acetylase responsible for IDH2 modification.…”

Section: Pcaf Acetylates Idh2 At Lysine Residue 180mentioning

confidence: 99%

P300/CBP‐associated factor regulates transcription and function of isocitrate dehydrogenase 2 during muscle differentiation

et al. 2018

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The epigenetic enzyme p300/CBP‐associated factor (PCAF) belongs to the GCN5‐related N‐acetyltransferase (GNAT) family together with GCN5. Although its transcriptional and post‐translational function is well characterized, little is known about its properties as regulator of cell metabolism. Here, we report the mitochondrial localization of PCAF conferred by an 85 aa mitochondrial targeting sequence (MTS) at the N‐terminal region of the protein. In mitochondria, one of the PCAF targets is the isocitrate dehydrogenase 2 (IDH2) acetylated at lysine 180. This PCAF‐regulated post‐translational modification might reduce IDH2 affinity for isocitrate as a result of a conformational shift involving predictively the tyrosine at position 179. Site‐directed mutagenesis and functional studies indicate that PCAF regulates IDH2, acting at dual level during myoblast differentiation: at a transcriptional level together with MyoD, and at a post‐translational level by direct modification of lysine acetylation in mitochondria. The latter event determines a decrease in IDH2 function with negative consequences on muscle fiber formation in C2C12 cells. Indeed, a MTS‐deprived PCAF does not localize into mitochondria, remains enriched into the nucleus, and contributes to a significant increase of muscle‐specific gene expression enhancing muscle differentiation. The role of PCAF in mitochondria is a novel finding shedding light on metabolic processes relevant to early muscle precursor differentiation.—Savoia, M., Cencioni, C., Mori, M., Atlante, S., Zaccagnini, G., Devanna, P., Di Marcotullio, L., Botta, B., Martelli, F., Zeiher, A. M., Pontecorvi, A., Farsetti, A., Spallotta, F., Gaetano, C. P300/CBP‐associated factor regulates transcription and function of isocitrate dehydrogenase 2 during muscle differentiation. FASEB J. 33, 4107–4123 (2019). http://www.fasebj.org

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SIRT3-Mediated Dimerization of IDH2 Directs Cancer Cell Metabolism and Tumor Growth

Cited by 73 publications

References 36 publications

Context-dependent activation of SIRT3 is necessary for anchorage-independent survival and metastasis of ovarian cancer cells

Context-dependent activation of SIRT3 is necessary for anchorage-independent survival and metastasis of ovarian cancer cells

2-Hydroxyglutarate in Cancer Cells

P300/CBP‐associated factor regulates transcription and function of isocitrate dehydrogenase 2 during muscle differentiation

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