Therapeutic Targeting of <i>MZF1‐AS1</i>/PARP1/E2F1 Axis Inhibits Proline Synthesis and Neuroblastoma Progression

Fang, Erhu; Wang, Xiaojing; Yang, Feng; Hu, Anpei; Wang, Jianqun; Li, Dan; Song, Huajie; Hong, Ming; Guo, Yanhua; Liu, Yang; Li, Hongjun; Zheng, Liduan; Tong, Qiangsong

doi:10.1002/advs.201900581

Cited by 29 publications

(45 citation statements)

References 51 publications

(57 reference statements)

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“…Recent studies on the role of Proline biosynthetic enzymes in neuroblastoma (NB) progression unravel a novel mechanism of transcriptional regulation of the genes coding for these enzymes (42). Specifically, myeloid zinc finger 1 (MZF1) and MZF1 antisense RNA1 (MZF1-AS1) have been identified as transcriptional regulators of ALDH18A1 and PYCR1.…”

Section: Transcriptional and Post-translational Regulation Of Pycr1 Amentioning

confidence: 99%

“…Mechanistically, MZF1AS1 promotes the up-regulation of both MZF1 and of other oncogenic genes through the interaction with poly(ADP-ribose) polymerase 1 (PARP1), thus facilitating its interaction with E2F transcription factor 1 (E2F1). Interestingly, MZF1, MZF1AS1, PARP1, and E2F1 are all associated with poor prognosis of NB patients, and blocking MZF1AS1 and PARP1 interaction, using a small peptide, or targeting MZF1AS1 suppresses Proline synthesis and tuomorigenesis, thus representing potential targets for NB therapy (42).…”

Section: Transcriptional and Post-translational Regulation Of Pycr1 Amentioning

confidence: 99%

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Proline Metabolism in Tumor Growth and Metastatic Progression

et al. 2020

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Cancer cells show a formidable capacity to survive under stringent conditions, to elude mechanisms of control, such as apoptosis, and to resist therapy. Cancer cells reprogram their metabolism to support uncontrolled proliferation and metastatic progression. Phenotypic and functional heterogeneity are hallmarks of cancer cells, which endow them with aggressiveness, metastatic capacity, and resistance to therapy. This heterogeneity is regulated by a variety of intrinsic and extrinsic stimuli including those from the tumor microenvironment. Increasing evidence points to a key role for the metabolism of non-essential amino acids in this complex scenario. Here we discuss the impact of proline metabolism in cancer development and progression, with particular emphasis on the enzymes involved in proline synthesis and catabolism, which are linked to pathways of energy, redox, and anaplerosis. In particular, we emphasize how proline availability influences collagen synthesis and maturation and the acquisition of cancer cell plasticity and heterogeneity. Specifically, we propose a model whereby proline availability generates a cycle based on collagen synthesis and degradation, which, in turn, influences the epigenetic landscape and tumor heterogeneity. Therapeutic strategies targeting this metabolic-epigenetic axis hold great promise for the treatment of metastatic cancers.

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Section: Transcriptional and Post-translational Regulation Of Pycr1 Amentioning

confidence: 99%

Section: Transcriptional and Post-translational Regulation Of Pycr1 Amentioning

confidence: 99%

Proline Metabolism in Tumor Growth and Metastatic Progression

et al. 2020

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“…E2F1 was a therapeutic target in neuroblastoma. Inhibition of E2F1 suppressed neuroblastoma progression [23]. Inhibition of ribosome singling pathway was also a promising strategy in neuroblastoma treatment [24].…”

Section: Discussionmentioning

confidence: 99%

Prognostic significance of MYCN related genes in pediatric neuroblastoma: a study based on TARGET and GEO datasets

Wang

et al. 2020

BMC Pediatr

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Background: Neuroblastoma patients with MYCN amplification are associated with poor prognosis. However, the prognostic relevance of MYCN associated genes in neuroblastoma is unclear. Methods: The expression profiles of MYCN associated genes were identified from Therapeutically Applicable Research to Generate Effective Treatments (TARGET) and Gene Expression Omnibus (GEO) datasets. Enriched transcription factors and signaling pathways were determined using gene set enrichment analysis (GSEA). Kaplan-Meier plotter was used to identify the prognostic relevance of MYCN associated genes. Multivariate cox regression and Spearman's correlation were used to determine the correlation coefficients of MYCN associated genes. Results: In TARGET and GSE85047 datasets, neuroblastoma patients with MYCN amplification were associated with worse prognosis. Transcription factor MYC was positively associated with MYCN amplification in GSEA assay. We identified 13 MYC target genes which were increased in neuroblastoma patients with MYCN amplification in TARGET, GSE19274 and GSE85047 datasets. Moreover, six out of the 13 MYC target genes ARMC6, DCTPP1, EIF4G1, ELOVL6, FBL and PRMT1 were associated with adverse prognosis in TARGET and GSE85047 datasets. Transcription factor E2F1 was up-regulated by MYCN amplification and associated with the poor prognosis of neuroblastoma. Furthermore, RPS19 in ribosome signaling pathway was also associated with MYCN amplification and correlated with the poor prognosis of neuroblastoma. At last, we showed that most of MYCN target genes were correlated with each other. However, EIF4G1 was an independent prognostic marker. And the prognostic effects of the combination of MYCN amplification and EIF4G1 expression were more significant than MYCN or EIF4G1 alone. Conclusions: MYCN target genes ARMC6, DCTPP1, EIF4G1, ELOVL6, FBL, PRMT1, E2F1 and RPS19 had significant prognostic effects in pediatric neuroblastoma. And neuroblastoma patients without MYCN amplification and low EIF4G1 expression had best prognosis.

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“…JPX is predicted to influence several immune-related processes, such as immune effector process, cell activation involved in immune response, the neutrophil degranulation pathway and the innate immune system pathway. The lncRNA MZF1‐AS1 was identified as a transcriptional regulator of proline synthesis and neuroblastoma progression and was associated with several pathways that regulate cell cycle, cell differentiation/development, proliferation and metabolism [ 47 ].…”

Section: Discussionmentioning

confidence: 99%

Investigation of circulating lncRNAs as potential biomarkers in chronic respiratory diseases

et al. 2020

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Background In the present study the blood expression level of inflammatory response and autoimmunity associated long non-coding RNAs (lncRNAs) were compared in patients with different chronic respiratory diseases and investigated whether they could be used as biomarkers in these diseases. Methods In the discovery cohort, the gene expression level of 84 lncRNAs were measured in the blood of 24 adult patients including healthy controls and patients with asthma and COPD. In the replication cohort the expression of 6 selected lncRNAs were measured in 163 subjects including healthy controls and adults with allergic rhinitis, asthma, COPD and children with asthma. It was evaluated whether these lncRNAs can be used as diagnostic biomarkers for any studied disease. With systems biology analysis the biological functions of the selected lncRNAs were predicted. Results In the discovery cohort, the mean expression of 27 lncRNAs showed nominally significant differences in at least one comparison. OIP5-AS1, HNRNPU, RP11-325K4.3, JPX, RP11-282O18.3, MZF1-AS1 were selected for measurement in the replication cohort. Three lncRNAs (HNRNPU, RP11-325K4.3, JPX) expressed significantly higher in healthy children than in adult controls. All the mean expression level of the 6 lncRNAs differed significantly between adult allergic rhinitis patients and controls. RP11-325K4.3, HNRNPU and OIP5-AS1 expressed higher in allergic asthma than in non-allergic asthma. COPD and asthma differed in the expression of RP11-325K4.3 from each other. In examining of the lncRNAs as biomarkers the weighted accuracy (WA) values were especially high in the comparison of healthy controls and patients with allergic rhinitis. OIP5-AS1 and JPX achieved 0.98 and 0.9 WA values, respectively, and the combination of the selected lncRNAs also resulted in a high performance (WA = 0.98). Altogether, OIP5-AS1 had the highest discriminative power in case of three out of six comparisons. Conclusion Differences were detected in the expression of circulating lncRNAs in chronic respiratory diseases. Some of these differences might be utilized as biomarkers and also suggest a possible role of these lncRNAs in the pathomechanism of these diseases. The lncRNAs and the associated pathways are potential therapeutic targets in these diseases, but naturally additional studies are needed for the confirmation of these results.

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Therapeutic Targeting of MZF1‐AS1/PARP1/E2F1 Axis Inhibits Proline Synthesis and Neuroblastoma Progression

Cited by 29 publications

References 51 publications

Proline Metabolism in Tumor Growth and Metastatic Progression

Proline Metabolism in Tumor Growth and Metastatic Progression

Prognostic significance of MYCN related genes in pediatric neuroblastoma: a study based on TARGET and GEO datasets

Investigation of circulating lncRNAs as potential biomarkers in chronic respiratory diseases

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