C/EBPβ-LIP induces cancer-type metabolic reprogramming by regulating the let-7/LIN28B circuit in mice

Ackermann, Tobias; Hartleben, Götz; Müller, Christine; Mastrobuoni, Guido; Groth, Marco; Sterken, Britt A.; Zaini, Mohamad Amr; Youssef, Sameh A.; Zuidhof, Hidde R.; Krauss, Sara Russo; Kortman, Gertrud; Haan, Gerald de; Bruin, Alain de; Wang, Zhao Qi; Platzer, Matthias; Kempa, Stefan; Calkhoven, Cornelis F.

doi:10.1038/s42003-019-0461-z

Cited by 16 publications

(28 citation statements)

References 70 publications

(86 reference statements)

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“…We examined the C/EBPβ isoform specific effects on cellular metabolism by measuring the extracellular acidification rate (ECAR) as an indicator for glycolytic flux, and the oxygen consumption rate (OCR) as a measure for mitochondrial metabolism (Seahorse XF96). Similar to what we showed earlier (Ackermann et al, 2019), experimental expression of LIP in immortalised Cebpb-knockout MEFs increased both basal and maximal ECAR, while expression of LAP had no effect on the ECAR (Fig. 1A).…”

Section: Lip Renders Cells Dependent On Glucose Metabolismsupporting

confidence: 89%

“…The MAS allows cancer cells to efficiently use the glycolysis for both energy production and anabolic processes and thereby can stimulate proliferation or survival upon glutamine starvation (Tajan et al, 2018). Our data indicate that LIP induces an increase in MAS activity that may be part of the oncogenic activities of LIP (Ackermann et al, 2019;Begay et al, 2015). Our preliminary experiments on regulation of the key factors SLC25A11…”

Section: Discussionmentioning

confidence: 72%

“…Moreover, LIP is highly expressed in breast cancer, ovarian cancer, colorectal cancer and anaplastic large cell lymphoma (Jundt et al, 2005;Quintanilla-Martinez et al, 2006;Rask et al, 2000;Sundfeldt et al, 1999;Zahnow et al, 2001;Zahnow et al, 1997). Recently, we demonstrated that LIP induces cancer metabolism with increased glycolysis and mitochondrial respiration through regulation of the let-7/LIN28B circuit (Ackermann et al, 2019).…”

Section: Introductionmentioning

confidence: 99%

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C/EBPβ-LIP dually activates glycolysis and the malate aspartate shuttle to maintain NADH/NAD+ homeostasis

Ackermann

Zuidhof

Kortman

et al. 2020

Preprint

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Oncogene-induced metabolic reprograming supports cell growth and proliferation. Yet, it also links cancer cell survival to certain metabolic pathways and nutrients. In order to synthesise amino acids and nucleotides de novo for growth and proliferation, cancer cells depend on glycolysis, the cytoplasmic oxidation of glucose, which generates necessary metabolic intermediates and ATP. During glycolysis, NAD+ is used as the oxidizing agent and is thereby reduced into NADH. To ensure high glycolysis rates and maintain NADH/NAD+ homeostasis, cytoplasmic NAD+ has to be regenerated. The mitochondria are the major sites of NADH reoxidation into NAD+ where NADH-derived electrons enter the electron transport chain for ATP production. Since NADH/NAD+ cannot cross membranes, the malate-aspartate shuttle (MAS) or the glycerol-3-phosphate shuttle (GPS) are used as intermediate electron carriers. In addition, cytoplasmic NAD+ is generated by NADH-electron transfer to pyruvate, reducing it to lactate (the Warburg effect). NADH/NAD+ homeostasis plays a pivotal role in cancer cell survival, but our knowledge about the involved regulatory mechanisms is still limited. Here, we show that the proto-oncogenic transcription factor C/EBPβ-LIP stimulates both glycolysis and the MAS. Inhibition of glycolysis with ongoing C/EBPβ-LIP-induced MAS activity results in NADH depletion and apoptosis that can be rescued by inhibiting either the MAS or other NADH-consuming processes. Therefore, beyond the discovery of C/EBPβ-LIP as a dual activator of glycolysis and the MAS, this study indicates that simultaneous inhibition of glycolysis and lowering of the NADH/NAD+ ratio may be considered to treat cancer.

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Section: Lip Renders Cells Dependent On Glucose Metabolismsupporting

confidence: 89%

Section: Discussionmentioning

confidence: 72%

Section: Introductionmentioning

confidence: 99%

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C/EBPβ-LIP dually activates glycolysis and the malate aspartate shuttle to maintain NADH/NAD+ homeostasis

Ackermann

Zuidhof

Kortman

et al. 2020

Preprint

Self Cite

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“…Deficiency of C/EBPβ in vitro inhibits adipogenesis, while its overexpression promotes adipogenesis, even without inducers [ 24 , 25 ]. Further, disruption of C/EBPβ expression in vivo causes reduced fat mass due to the impairment of adipose tissue development [ 26 ]. Thus, C/EBPβ is an essential early adipogenic factor to promote adipogenesis [ 27 ].…”

Section: Introductionmentioning

confidence: 99%

HMGB2 orchestrates mitotic clonal expansion by binding to the promoter of C/EBPβ to facilitate adipogenesis

et al. 2021

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High-mobility group box 2 (HMGB2) is an abundant, chromatin-associated protein that plays an essential role in the regulation of transcription, cell proliferation, differentiation, and tumorigenesis. However, the underlying mechanism of HMGB2 in adipogenesis remains poorly known. Here, we provide evidence that HMGB2 deficiency in preadipocytes impedes adipogenesis, while overexpression of HMGB2 increases the potential for adipogenic differentiation. Besides, depletion of HMGB2 in vivo caused the decrease in body weight, white adipose tissue (WAT) mass, and adipocyte size. Consistently, the stromal vascular fraction (SVF) of adipose tissue derived from hmgb2−/− mice presented impaired adipogenesis. When hmgb2−/− mice were fed with high-fat diet (HFD), the body size, and WAT mass were increased, but at a lower rate. Mechanistically, HMGB2 mediates adipogenesis via enhancing expression of C/EBPβ by binding to its promoter at “GGGTCTCAC” specifically during mitotic clonal expansion (MCE) stage, and exogenous expression of C/EBPβ can rescue adipogenic abilities of preadipocytes in response to HMGB2 inhibition. In general, our findings provide a novel mechanism of HMGB2-C/EBPβ axis in adipogenesis and a potential therapeutic target for obesity.

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“…S7B). C/EBPβ is thought as an positive regulator of glycolysis inducing cancer-type metabolic reprogramming 50,51 . Overall, all the above investigations need to be further proved in future research.…”

Section: Discussionmentioning

confidence: 99%

Multi-omics analysis identifies FoxO1 as a regulator of macrophage function through metabolic reprogramming

Yan

Bian

et al. 2020

Cell Death Dis

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Macrophages are plastic cells that can switch among different states according to bioenergetic or biosynthetic requirements. Our previous work demonstrated that the transcription factor Forkhead Box Protein 1 (FoxO1) plays a pivotal role in regulating the function of macrophages, but the underlying mechanisms are still unclear. Here we identify FoxO1 as a regulator of macrophage function through metabolic reprogramming. Transcriptomic and proteomic analyses showed that the deficiency of FoxO1 results in an alternatively activated (M2) phenotype of macrophages, with lower expression of inflammatory response- and migration-associated genes. Using the high content screening and analysis technology, we found that deletion of FoxO1 in macrophages slows their migration rate and impairs their function to limit tumor cell growth in vitro. Next, we demonstrated that glycolysis is inhibited in FoxO1-deficient macrophages, which leads to the observed functional changes and the reduced tumor suppression capability. This prospective study shows that FoxO1 serves as a bridge between metabolism and macrophage function.

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C/EBPβ-LIP induces cancer-type metabolic reprogramming by regulating the let-7/LIN28B circuit in mice

Cited by 16 publications

References 70 publications

C/EBPβ-LIP dually activates glycolysis and the malate aspartate shuttle to maintain NADH/NAD+ homeostasis

C/EBPβ-LIP dually activates glycolysis and the malate aspartate shuttle to maintain NADH/NAD+ homeostasis

HMGB2 orchestrates mitotic clonal expansion by binding to the promoter of C/EBPβ to facilitate adipogenesis

Multi-omics analysis identifies FoxO1 as a regulator of macrophage function through metabolic reprogramming

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