Wild-type IDH2 contributes to Epstein–Barr virus-dependent metabolic alterations and tumorigenesis

Shi, Feng; He, Ya; Li, Jiangjiang; Tang, Min; Li, Yueshuo; Xie, Longlong; Zhao, Lin; Hu, Jianmin; Zhou, Min; Liu, Na; Fan, Jia; Zhou, Jian; Gao, Qiang; Qiu, Shuang; Wu, Wei‐Zhong; Zhang, Xin; Jia, Wei‐Hua; Bode, Ann M.; Cao, Yang

doi:10.1016/j.molmet.2020.02.009

Cited by 21 publications

(24 citation statements)

References 42 publications

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“…Interestingly, a recent study indicated that C-MYC could promote IDH2 transcription associated with Epstein-Barr virus (EBV)-related tumorigenesis [ 51 ]. This observation, together with our findings that α-KG could regulate c-Myc expression, suggests a possibility that c-Myc and wt-IDH2 could form a positive feedback loop to promote leukemia development: C-MYC enhances the expression of IDH2, which converts α-KG to isocitrate and thus maintains cellular α-KG at low level.…”

Section: Discussionmentioning

confidence: 99%

Reductive TCA cycle catalyzed by wild-type IDH2 promotes acute myeloid leukemia and is a metabolic vulnerability for potential targeted therapy

Zeng

Tian

et al. 2022

J Hematol Oncol

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Background Isocitrate dehydrogenase-2 (IDH2) is a mitochondrial enzyme that catalyzes the metabolic conversion between isocitrate and alpha-ketoglutarate (α-KG) in the TCA cycle. IDH2 mutation is an oncogenic event in acute myeloid leukemia (AML) due to the generation of 2-hydroxyglutarate. However, the role of wild-type IDH2 in AML remains unknown, despite patients with it suffer worse clinical outcome than those harboring mutant type. Methods IDH2 expression in AML cell lines and patient samples was evaluated by RT-qPCR, western blotting and database analyses. The role of wild-type IDH2 in AML cell survival and proliferation was tested using genetic knockdown and pharmacological inhibition in AML cells and animal models. LC–MS, GC–MS, isotope metabolic tracing, and molecular analyses were performed to reveal the underlying mechanisms. Results We found that wild-type IDH2 was overexpressed in AML and played a major role in promoting leukemia cell survival and proliferation in vitro and in vivo. Metabolomic analyses revealed an active IDH2-mediated reductive TCA cycle that promoted the conversion of α-KG to isocitrate/citrate to facilitate glutamine utilization for lipid synthesis in AML cells. Suppression of wild-type IDH2 by shRNA resulted in elevated α-KG and decreased isocitrate/citrate, leading to reduced lipid synthesis, a significant decrease in c-Myc downregulated by α-KG, and an inhibition of AML viability and proliferation. Importantly, pharmacological inhibition of IDH2 showed significant therapeutic effect in mice inoculated with AML cells with wt-IDH2 and induced a downregulation of C-MYC in vivo. Conclusions Wt-IDH2 is an essential molecule for AML cell survival and proliferation by promoting conversion of α-KG to isocitrate for lipid synthesis and by upregulating c-Myc expression and could be a potential therapeutic target in AML.

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Section: Discussionmentioning

confidence: 99%

Reductive TCA cycle catalyzed by wild-type IDH2 promotes acute myeloid leukemia and is a metabolic vulnerability for potential targeted therapy

Zeng

Tian

et al. 2022

J Hematol Oncol

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“… 69 Recently, we revealed that EBV-LMP1 promotes the accumulation of fumarate and 2-HG, and the reduction of α-KG, which consequently leads to the inactivation of TETs. 70 , 71 Moreover, 2-HG could also regulate DNMT1 activity by enhancing its binding to selected DNA regions. 72 EBV infection might tip the balance in DNA methylation-demethylation dynamics (Fig.…”

Section: Dna Methylation Alterations and Clinical Applications In Ebvmentioning

confidence: 99%

Targeting the signaling in Epstein–Barr virus-associated diseases: mechanism, regulation, and clinical study

Cao

Xie

Shi

et al. 2021

Sig Transduct Target Ther

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Epstein–Barr virus-associated diseases are important global health concerns. As a group I carcinogen, EBV accounts for 1.5% of human malignances, including both epithelial- and lymphatic-originated tumors. Moreover, EBV plays an etiological and pathogenic role in a number of non-neoplastic diseases, and is even involved in multiple autoimmune diseases (SADs). In this review, we summarize and discuss some recent exciting discoveries in EBV research area, which including DNA methylation alterations, metabolic reprogramming, the changes of mitochondria and ubiquitin-proteasome system (UPS), oxidative stress and EBV lytic reactivation, variations in non-coding RNA (ncRNA), radiochemotherapy and immunotherapy. Understanding and learning from this advancement will further confirm the far-reaching and future value of therapeutic strategies in EBV-associated diseases.

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“…The c-Myc-induced overexpression of non-coding RNAs contributes to the regulation of downstream genes, further enhancing the metastasis and proliferation of NPC [ 46 – 50 ]. c-Myc also increases the levels of metabolic-related proteins for the execution of metabolic reprogramming, which in turn leads to metastasis and proliferation [ 51 , 52 ]. Furthermore, c-Myc interacts with signaling networks associated with NPC metastasis and proliferation, including the PI3K/Akt [ 53 ] and JNK/c-JUN [ 54 , 55 ] pathways, exacerbating the malignant progression of NPC.…”

Section: Discussionmentioning

confidence: 99%

Splicing factor derived circular RNA circCAMSAP1 accelerates nasopharyngeal carcinoma tumorigenesis via a SERPINH1/c-Myc positive feedback loop

Wang

Yan

et al. 2022

Mol Cancer

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Background Circular RNAs play an important role in tumor genesis and progression, but they have not been sufficiently studied in patients with nasopharyngeal carcinoma (NPC). Methods The circular RNA, circCAMSAP1, was screened in NPC cells by RNA sequencing analysis. The expression of circCAMSAP1 in NPC tissues was examined by real-time quantitative polymerase chain reaction (RT-qPCR) and in situ hybridization. Wound-healing, transwell, MTT and flow cytometry assays, and nude mouse tumor models were used to explore the effect of circCAMSAP1 on proliferation and metastasis of NPC in vitro or in vivo. The downstream proteins regulated by circCAMSAP1 were screened using mass spectrometry. The interaction between circCAMSAP1 and the SERPINH1 mRNA was identified using the circular RNA immunoprecipitation method and the luciferase reporter assay. The interaction between SERPINH1 and transcription factor c-Myc was verified through Co-immunoprecipitation (Co-IP) and immunofluorescence. The effect of c-Myc on the generation of circCAMSAP1 was examined through RT-qPCR and chromatin immunoprecipitation. Finally, the splicing factors that promote the production of circCAMSAP1 were explored by RT-qPCR and RNA immunoprecipitation (RIP). Results We found that circCAMSAP1 was highly expressed in NPC tissues and promoted NPC proliferation and metastasis. Additionally, circCAMSAP1 promoted SERPINH1 expression through improved SERPINH1 mRNA stability by binding to the 3′-untranslated region (3’UTR) of SERPINH1. Highly expressed SERPINH1 reduced the ubiquitination-degradation rate of c-Myc, causing increased tumorigenesis. Meanwhile, c-Myc, cooperating with splicing factor 10 (SRSF10), could also promote CAMSAP1 pre-mRNA transcription and back-splicing, forming a positive feedback of circCAMSAP1 production, resulting in the proliferation and metastasis of NPC. Conclusions Our findings revealed that circCAMSAP1 promotes NPC proliferation and metastasis by binding to the 3’UTR of SERPINH1, suggesting that the positive feedback of circCAMSAP1-SERPINH1-c-Myc may serve as a prognostic biomarker or therapeutic target in patients with NPC.

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Wild-type IDH2 contributes to Epstein–Barr virus-dependent metabolic alterations and tumorigenesis

Cited by 21 publications

References 42 publications

Reductive TCA cycle catalyzed by wild-type IDH2 promotes acute myeloid leukemia and is a metabolic vulnerability for potential targeted therapy

Reductive TCA cycle catalyzed by wild-type IDH2 promotes acute myeloid leukemia and is a metabolic vulnerability for potential targeted therapy

Targeting the signaling in Epstein–Barr virus-associated diseases: mechanism, regulation, and clinical study

Splicing factor derived circular RNA circCAMSAP1 accelerates nasopharyngeal carcinoma tumorigenesis via a SERPINH1/c-Myc positive feedback loop

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