Serine Biosynthesis Pathway Supports MYC–miR-494–EZH2 Feed-Forward Circuit Necessary to Maintain Metabolic and Epigenetic Reprogramming of Burkitt Lymphoma Cells

Białopiotrowicz, Emilia; Noyszewska‐Kania, Monika; Kachamakova‐Trojanowska, Neli; Łoboda, Agnieszka; Cybulska, Magdalena; Grochowska, Aleksandra; Kopczyński, Michał; Mikula, Michał; Prochorec‐Sobieszek, Monika; Firczuk, Małgorzata; Graczyk-Jarzynka, Agnieszka; Zagożdżon, Radosław; Ząbek, Adam; Młynarz, Piotr; Dulak, Józef; Górniak, Patryk; Szydłowski, Maciej; Pyziak, Karolina; Martyka, Justyna; Sroka-Porada, Agnieszka; Jabłońska, Ewa; Polak, Anna; Kowalczyk, Piotr; Szumera‐Ciećkiewicz, Anna; Chapuy, Bjoern; Rzymski, Tomasz; Brzózka, Krzysztof; Juszczyński, Przemysław

doi:10.3390/cancers12030580

Cited by 42 publications

(36 citation statements)

References 48 publications

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“…In addition, EZH2 was shown to promote MYC expression by inhibiting the MYC-targeting miR-494-3p, resulting in a positive feedback loop between MYC, miR-26a/b-5p, EZH2, and miR-494-3p, which ensured high MYC levels and proliferation of BL [17,42]. A recently published study also confirmed the interplay between MYC, miR-494-3p, and EZH2 in BL [43].…”

Section: Discussionmentioning

confidence: 76%

The miR-26b-5p/KPNA2 Axis Is an Important Regulator of Burkitt Lymphoma Cell Growth

Niu

Kazimierska

Nolte

et al. 2020

Cancers

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The expression of several microRNAs (miRNAs) is known to be changed in Burkitt lymphoma (BL), compared to its normal counterparts. Although for some miRNAs, a role in BL was demonstrated, for most of them, their function is unclear. In this study, we aimed to identify miRNAs that control BL cell growth. Two BL cell lines were infected with lentiviral pools containing either 58 miRNA inhibitors or 44 miRNA overexpression constructs. Eighteen constructs showed significant changes in abundance over time, indicating that they affected BL growth. The screening results were validated by individual green fluorescent protein (GFP) growth competition assays for fifteen of the eighteen constructs. For functional follow-up studies, we focused on miR-26b-5p, whose overexpression inhibited BL cell growth. Argonaute 2 RNA immunoprecipitation (Ago2-IP) in two BL cell lines revealed 47 potential target genes of miR-26b-5p. Overlapping the list of putative targets with genes showing a growth repression phenotype in a genome-wide CRISPR/Cas9 knockout screen, revealed eight genes. The top-5 candidates included EZH2, COPS2, KPNA2, MRPL15, and NOL12. EZH2 is a known target of miR-26b-5p, with oncogenic properties in BL. The relevance of the latter four targets was confirmed using sgRNAs targeting these genes in individual GFP growth competition assays. Luciferase reporter assay confirmed binding of miR-26b-5p to the predicted target site for KPNA2, but not to the other genes. In summary, we identified 18 miRNAs that affected BL cell growth in a loss- or gain-of-function screening. A tumor suppressor role was confirmed for miR-26b-5p, and this effect could at least in part be attributed to KPNA2, a known regulator of OCT4, c-jun, and MYC.

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Section: Discussionmentioning

confidence: 76%

The miR-26b-5p/KPNA2 Axis Is an Important Regulator of Burkitt Lymphoma Cell Growth

Niu

Kazimierska

Nolte

et al. 2020

Cancers

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“…Additional chromosomal abnormalities, recurrent abnormally expressed transcripts and/or gene mutations are also detected in BL/BAL patients and have roles in the initiation, progression and aggressiveness of the disease [5]. For instance, somatic mutations of TCF3 can activate the PI3K/MAPK/MTOR pathway, in part by increasing a tonic form of B cell receptor signaling, and patients with germline mutations in the SH2 domain protein 1A gene (SH2D1A) suffer from an increased risk of BL/BAL [6].…”

Section: Introductionmentioning

confidence: 99%

Genomic signatures in pediatric advanced stage Burkitt lymphoma/leukemia in a Chinese population detected by next generation sequencing

Xiao

Yin

et al. 2021

Arch Med Sci

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IntroductionBurkitt lymphoma/leukemia (BL/BAL) is the most common lymphoma in children, and the sporadic subtype is dominant in Chinese populations. MYC gene translocations are essential for sporadic BL/BAL (sBL/BAL), but other gene mutations also play important roles in sBL/BAL.Material and methodsClinical data of ten Chinese children with sBL/BAL were collected, next generation sequencing of tumor tissues was carried out. Cases of BL and diffuse large B cell lymphoma (DLBCL) were collected from a database, bioinformatics analysis was conductedResultsNine boys and one girl were enrolled, the average age at diagnosis was 100.10±13.39m; MYC rearrangements were confirmed. The patients received combination treatment of chemotherapy and rituximab. All patients achieved complete remission and were alive without relapse. Germline causal gene mutations were detected in four (40%) patients by whole-exome sequencing; ID3, BRCA2, ARID1A and SMARCA4 mutations, in addition to MYC mutations, were the most common somatic mutations. Gene functions in etiology were different between the BL and DLBCL datasets. The identified mutated genes were enriched and connected by GO or KEGG pathways, it seemed that the PI3K-Akt signaling pathway played important roles in the etiology of sBL/BAL; the EGFR-TKI resistance pathway was also analyzed.ConclusionsThe different gene mutations might be index to identify BL or DLBCL in case of difficult pathologic samples. Molecular hallmark of sBL/BAL is MYC translocation, whereas additional gene mutations also occur and play roles in the progression of the disease. sBL/BAL might be controlled by curbing the PI3K-Akt signaling pathway; the EGFR-TKI treatment might not be helpful in sBL/BAL.

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“…Moreover, the increased fatty acid catabolism was associated with a decrease of trimethylation of histone H3 lysine 27 (H3K27me3) [15,16] which was also an independent prognostic factor for breast cancer [17,18] . Furthermore, many studies have found that the decreased level of H3K27me3 suppressed the transcription of oncogene MYC which was essential for the expression of GLS [19,20] . Thus, the relationship between GLS and H3K27me3 was intriguing, which may affect the prognostic role of GLS on breast cancer.…”

Section: Introductionmentioning

confidence: 99%

Interaction of H3K27me3 and Glutaminase 1 Expression on Breast Cancer Prognosis by Menopausal Status: a Cohort Study

Zhou

Chen

Yang

et al. 2021

Preprint

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Background: Glutaminase 1 (GLS) is a potential therapeutic target for breast cancer; although GLS inhibitors have been developed, only a few subjects responded well to the therapy. Considering that the expression of trimethylation of histone H3 lysine 27 (H3K27me3) and menopausal status have been closely linked to the role of GLS, we tried to examine the modification effects of H3K27me3 and menopausal status on GLS to breast cancer prognosis, which would be helpful to identify the more suitable patients to the GLS inhibitors.Methods: Data for 963 women diagnosed with primary invasive breast cancer between 2008 and 2015 were analyzed. H3K27me3 and GLS expression in tumors were evaluated with tissue microarrays by immunohistochemistry. Hazard ratios (HRs) and their 95% confidence intervals (CIs) for overall survival (OS) and progression-free survival (PFS) were estimated using univariable and multivariable Cox regression models. The interaction was assessed on multiplicative scale by stratification analysis.Results: After a median follow-up of 70.6 months (interquartile range: 45.6-103.9), we confirmed the association between H3K27me3 and both outcomes (HR =0.57, 95% CI: 0.37-0.86 for OS; HR =0.66, 95% CI: 0.48-0.91 for PFS) and found that the prognostic roles of GLS were not statistically significant in the overall patients. There was a beneficial prognostic effect of GLS expression on OS for those with low H3K27me3 level (HR =0.50, 95% CI: 0.20-1.28) but an adverse prognostic effect for those with high H3K27me3 level (HR =3.90, 95% CI: 1.29-11.78) among premenopausal women, and the interaction was significant (Pinteraction =0.003). Similar pattern was further observed for PFS (HR =0.44, 95% CI: 0.20-0.95 for low H3K27me3 level, HR =1.35, 95% CI: 0.74-2.48 for high H3K27me3 level, Pinteraction =0.024). The interaction didn’t occur among postmenopausal women.Conclusions: This study revealed the modification effects of H3K27me3 and menopausal status on GLS to breast cancer prognosis, which would help optimize the medication strategies related to GLS inhibitors.

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Serine Biosynthesis Pathway Supports MYC–miR-494–EZH2 Feed-Forward Circuit Necessary to Maintain Metabolic and Epigenetic Reprogramming of Burkitt Lymphoma Cells

Cited by 42 publications

References 48 publications

The miR-26b-5p/KPNA2 Axis Is an Important Regulator of Burkitt Lymphoma Cell Growth

The miR-26b-5p/KPNA2 Axis Is an Important Regulator of Burkitt Lymphoma Cell Growth

Genomic signatures in pediatric advanced stage Burkitt lymphoma/leukemia in a Chinese population detected by next generation sequencing

Interaction of H3K27me3 and Glutaminase 1 Expression on Breast Cancer Prognosis by Menopausal Status: a Cohort Study

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