C/EBPβ-1 promotes transformation and chemoresistance in Ewing sarcoma cells

Gardiner, Jamie; Abegglen, Lisa M.; Huang, Xiaomeng; Carter, Bryce E.; Schackmann, Elizabeth A.; Stucki, Marcus; Paxton, Christian N.; Randall, R. Lor; Amatruda, James F.; Putnam, Angelica R.; Kovar, Heinrich; Lessnick, Stephen L.; Schiffman, Joshua D.

doi:10.18632/oncotarget.14847

Cited by 14 publications

(17 citation statements)

References 38 publications

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“…59,60 In Ewing sarcoma and ovarian cancer, CEBPB could promote tumor cell resistance to chemotherapy. 61,62 In this study, we found that CEBPB promotes the transcription of CPT1A and activates FAO. We confirmed that PGC1α binds to CEBPB and is co-localized to the promoter of CPT1A; knockdown of CEBPB sensitized NPC cells to radiation therapy.…”

Section: Discussionsupporting

confidence: 52%

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PGC1α/CEBPB/CPT1A axis promotes radiation resistance of nasopharyngeal carcinoma through activating fatty acid oxidation

Tan

Shi

et al. 2019

Cancer Science

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The PPAR coactivator‐1α (PGC1α) is an important transcriptional co‐activator in control of fatty acid metabolism. Mitochondrial fatty acid oxidation (FAO) is the primary pathway for the degradation of fatty acids and promotes NADPH and ATP production. Our previous study demonstrated that upregulation of carnitine palmitoyl transferase 1 A (CPT1A), the key regulator of FAO, promotes radiation resistance of nasopharyngeal carcinoma (NPC). In this study, we found that high expression of PGC1α is associated with poor overall survival in NPC patients after radiation treatment. Targeting PGC1α could sensitize NPC cells to radiotherapy. Mechanically, PGC1α binds to CCAAT/enhancer binding protein β (CEBPB), a member of the transcription factor family of CEBP, to promote CPT1A transcription, resulting in activation of FAO. Our results revealed that the PGC1α/CEBPB/CPT1A/FAO signaling axis promotes radiation resistance of NPC. These findings indicate that the expression of PGC1α could be a prognostic indicator of NPC, and targeting FAO in NPC with high expression of PGC1α might improve the therapeutic efficacy of radiotherapy.

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Section: Discussionsupporting

confidence: 52%

“…CEBPB expression is associated with overall survival in breast cancer and gastric cancer patients . In Ewing sarcoma and ovarian cancer, CEBPB could promote tumor cell resistance to chemotherapy . In this study, we found that CEBPB promotes the transcription of CPT1A and activates FAO.…”

Section: Discussionmentioning

confidence: 51%

PGC1α/CEBPB/CPT1A axis promotes radiation resistance of nasopharyngeal carcinoma through activating fatty acid oxidation

Tan

Shi

et al. 2019

Cancer Science

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“…The differences in the viscosity between DMEM with and without LA717 were, although statistically significant, not noticeable in the practical handling, as both were able to be handled as a liquid. By comparison, the viscosity of DMEM with agarose was far greater at 0.4%, the concentration employed for soft agar colony formation assays 23 (Supplementary Table S2 ). Furthermore, addition of 0.03% methyl cellulose to the medium resulted in a larger increase in viscosity than 0.03% LA717.…”

Section: Resultsmentioning

confidence: 99%

Novel 3D Liquid Cell Culture Method for Anchorage-independent Cell Growth, Cell Imaging and Automated Drug Screening

Abe-Fukasawa

Otsuka

Aihara

et al. 2018

Sci Rep

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Cells grown in three-dimensional (3D) cultures are more likely to have native cell-cell and cell-matrix interactions than in 2D cultures that impose mechanical constraints to cells. However, most 3D cultures utilise gel matrix which, while serving as a scaffold, limits application due to its solid and opaque nature and inconsistency in cell exposure to exogenous signals. In 3D culture without gel matrix, cells tend to adhere to each other and form clumps with necrotic zone at the centre, making them unsuitable for analyses. Here we report that addition of low-molecular-weight agar named LA717 to culture media allows cells to grow as dispersed clonal spheroids in 3D. LA717 maintains cells dispersed and settled to the bottom of the medium while keeping the medium clear with little additional viscosity, making it suitable for microscopic observation. Importantly, cancer spheroids formed in LA717-containing medium show higher sensitivity to anti-cancer drugs such as Trametinib and MK-2206 that are not as effective in 2D. Because of the small and consistent size of spheroids, cell viability and drug toxicity are readily detectable in automated imaging analysis. These results demonstrate that LA717 offers a novel 3D culture system with great in vivo reflection and practicality.

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“…It is therefore notable that Trib1 knockdown suppressed Ewing sarcoma cell growth concomitant with increased levels of C/EBPβ. A recent study suggested that overexpression of C/EBPβ increased the transformation activity of Ewing sarcoma cells, although it did not affect cell proliferation or viability, suggesting that a complex feedback loop may exist in C/EBPβ regulation. Nrg1 encodes neuregulin 1 or heregulin, the predominant ligand for ERBB3, and NRG1/ERBB signals are important in cellular development such as for Schwann cells and the cardiovascular system .…”

Section: Discussionmentioning

confidence: 99%

EWS‐FLI1 regulates a transcriptional program in cooperation with Foxq1 in mouse Ewing sarcoma

et al. 2018

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EWS‐FLI1 constitutes an oncogenic transcription factor that plays key roles in Ewing sarcoma development and maintenance. We have recently succeeded in generating an ex vivo mouse model for Ewing sarcoma by introducing EWS‐FLI1 into embryonic osteochondrogenic progenitors. The model well recapitulates the biological characteristics, small round cell morphology, and gene expression profiles of human Ewing sarcoma. Here, we clarified the global DNA binding properties of EWS‐FLI1 in mouse Ewing sarcoma. GGAA microsatellites were found to serve as binding sites of EWS‐FLI1 albeit with less frequency than that in human Ewing sarcoma; moreover, genomic distribution was not conserved between human and mouse. Nevertheless, EWS‐FLI1 binding sites within GGAA microsatellites were frequently associated with the histone H3K27Ac enhancer mark, suggesting that EWS‐FLI1 could affect global gene expression by binding its target sites. In particular, the Fox transcription factor binding motif was frequently observed within EWS‐FLI1 peaks and Foxq1 was identified as the cooperative partner that interacts with the EWS portion of EWS‐FLI1. Trib1 and Nrg1 were demonstrated as target genes that are co‐regulated by EWS‐FLI1 and Foxq1, and are important for cell proliferation and survival of Ewing sarcoma. Collectively, our findings present novel aspects of EWS‐FLI1 function as well as the importance of GGAA microsatellites.

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C/EBPβ-1 promotes transformation and chemoresistance in Ewing sarcoma cells

Cited by 14 publications

References 38 publications

PGC1α/CEBPB/CPT1A axis promotes radiation resistance of nasopharyngeal carcinoma through activating fatty acid oxidation

PGC1α/CEBPB/CPT1A axis promotes radiation resistance of nasopharyngeal carcinoma through activating fatty acid oxidation

Novel 3D Liquid Cell Culture Method for Anchorage-independent Cell Growth, Cell Imaging and Automated Drug Screening

EWS‐FLI1 regulates a transcriptional program in cooperation with Foxq1 in mouse Ewing sarcoma

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