EZH2 regulates neuroblastoma cell differentiation via NTRK1 promoter epigenetic modifications

Li, Zhenghao; Takenobu, Hisanori; Setyawati, Amallia Nuggetsiana; Akita, Nobuhiro; Haruta, Masayuki; Satoh, Shunpei; Shinno, Yoshitaka; Chikaraishi, Koji; Mukae, Kyosuke; Akter, Jesmin; Sugino, Ryuichi P.; Nakazawa, Atsuko; Nakagawara, Akira; Aburatani, Hiroyuki; Ohira, Miki; Kamijo, Takehiko

doi:10.1038/s41388-018-0133-3

Cited by 62 publications

(64 citation statements)

References 47 publications

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“…EZH2 on the other hand is a core component of polycomb repressive complex 2 and responsible for the catalysis of H3K27 tri-methylation. EZH2 plays an essential role in tumorigenesis in neuroblastoma and aberrant expression of EZH2 is strongly associated with poor prognosis [21][22][23] . Next, we employed gene ontology (GO) analysis on gene signatures created for each of the three cell states.…”

Section: Transitional Neuroblasts Are Defined By An Aggressive Neurodmentioning

confidence: 99%

Single-cell RNA-sequencing of peripheral neuroblastic tumors reveals an aggressive transitional cell state at the junction of an adrenergic-mesenchymal transdifferentiation trajectory

Yuan

Seneviratne

et al. 2020

Preprint

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Peripheral neuroblastic tumors (PNTs) are the most common extracranial solid tumors in early childhood.They represent a spectrum of neural crest derived tumors including neuroblastoma, ganglioneuroblastoma and ganglioneuroma. PNTs exhibit heterogeneity due to interconverting malignant cell states described as adrenergic/nor-adrenergic or mesenchymal/neural crest cell in origin. The factors determining individual patient levels of tumor heterogeneity, their impact on the malignant phenotype, and the presence of other cell states are unknown. Here, single-cell RNA-sequencing analysis of 4267 cells from 7 PNTs demonstrated extensive transcriptomic heterogeneity. Trajectory modelling showed that malignant neuroblasts move between adrenergic and mesenchymal cell states via a novel state that we termed a "transitional" phenotype. Transitional cells are characterized by gene expression programs linked to a sympathoadrenal development, and aggressive tumor phenotypes such as rapid proliferation and tumor dissemination. Among primary bulk tumor patient cohorts, high expression of the transitional gene signature was highly predictive of poor prognosis when compared to adrenergic and mesenchymal expression patterns. High transitional gene expression in neuroblastoma cell lines identified a similar transitional H3K27-acetylation super-enhancer landscape, supporting the concept that PNTs have phenotypic plasticity and transdifferentiation capacity. Additionally, examination of PNT microenvironments, found that neuroblastomas contained low immune cell infiltration, high levels of non-inflammatory macrophages, and low cytotoxic T lymphocyte levels compared with more benign PNT subtypes. Modeling of cell-cell signaling in the tumor microenvironment predicted specific paracrine effects toward the various subtypes of malignant cells, suggesting further cell-extrinsic influences on malignant cell phenotype. Collectively, our study reveals the presence of a previously unrecognized transitional cell state with high malignant potential and an immune cell architecture which serve both as potential biomarkers and therapeutic targets.Introduction Peripheral neuroblastic tumors (PNTs) represent a spectrum of tumors derived from the neural crest and account up to 8-10% of all pediatric malignancies. A salient feature of PNTs is a heterogeneous clinical course ranging from spontaneous regression to persistent disease progression 1 . Histologically, PNTs comprise four variants, including neuroblastoma (NB), ganglioneuroblastoma nodular (GNBn), ganglioneuroblastoma intermixed (GNBi), and ganglioneuroma (GN) 1 . GN and GNBi are low-grade in nature and usually curable by surgical resection alone 2 . In contrast, the most common subtype; NB is often lethal. Despite intensive treatments, the long-term survival of high-risk NB is less than 50% 3 .Around half of high-risk patients relapse after initial treatment response, and salvage therapies for relapsed patients are rarely effective 1 . Moreover, genomics studies comparing longitudinal samples f...

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Section: Transitional Neuroblasts Are Defined By An Aggressive Neurodmentioning

confidence: 99%

Single-cell RNA-sequencing of peripheral neuroblastic tumors reveals an aggressive transitional cell state at the junction of an adrenergic-mesenchymal transdifferentiation trajectory

Yuan

Seneviratne

et al. 2020

Preprint

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“…In the study of underlying mechanism of pathogenesis of thyroid cancer, Hou et al have elucidated that the increase of H3K27me3 induced by BRAF V600E mutation was achieved by enhancing the expression of c‐Myc followed by the expression of EZH2 . Besides, tazemetostat‐induced differentiation has also been carried out by reducing H3K27me3 via directly inhibiting EZH2 activity in neuroblastoma . Therefore, the combination of MAPKi with tazemetostat in our study not only reduced the expression of EZH2 but inhibited its activity as well, yielding robust reduction of the downstream H3K27me3, which effectively helped to enhance the differentiation of BRAF V600E ‐mutant PTC cells.…”

Section: Discussionmentioning

confidence: 55%

“…15 Besides, tazemetostat-induced differentiation has also been carried out by reducing H3K27me3 via directly inhibiting EZH2 activity in neuroblastoma. 16 Therefore, the combination of MAPKi with tazemetostat in our study not only reduced the expression of EZH2 but inhibited its activity as well, yielding robust reduction of the downstream H3K27me3, which effectively helped to enhance the differentiation of BRAF V600E -mutant PTC cells. In control cell line (TPC-1), H3K27me3 was decreased when tazemetostat was coupled with MAPKi compared with MAPKi monotherapy, but dabrafenib did not intensify the impact of tazemetostat on H3K27me3, hinting a tazemetostat-predominant effect.…”

Section: Encouraged By Enhancement Of Transcription and Translation Ofmentioning

confidence: 60%

“…15 Conversely, the decrease of H3K27me3 via reducing the expression of EZH2 by MAPKi was fulfilled in thyroid cancer, and the differentiation markers in melanoma and neuroblastoma could be increased by EZH2 knockdown. 12,15,16 However, the differentiation efficacy of EZH2 inhibitor alone or combined with MAPKi in thyroid cancer remains unknown. We, therefore, conceived this study to evaluate the differentiation efficacy of EZH2 inhibitor, assess the impact on differentiation induced by EZH2 inhibitor combined with MAPKi and elucidate the underlying mechanisms in PTC cell lines.…”

Section: Furthermore Mapk Signal Aberrant Activation By Braf V600ementioning

confidence: 99%

“…Furthermore, MAPK signal aberrant activation by BRAF V600E has also been demonstrated to increase the level of H3K27me3 through increasing the expression of Ezh2 in thyroid cancer . Conversely, the decrease of H3K27me3 via reducing the expression of EZH2 by MAPKi was fulfilled in thyroid cancer, and the differentiation markers in melanoma and neuroblastoma could be increased by EZH2 knockdown . However, the differentiation efficacy of EZH2 inhibitor alone or combined with MAPKi in thyroid cancer remains unknown.…”

Section: Introductionmentioning

confidence: 99%

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Combined tazemetostat and MAPKi enhances differentiation of papillary thyroid cancer cells harbouring BRAF^V600E by synergistically decreasing global trimethylation of H3K27

Cheng

et al. 2020

J Cellular Molecular Medi

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Clinical efficacy of differentiation therapy with mitogen‐activated protein kinase inhibitors (MAPKi) for lethal radioiodine‐refractory papillary thyroid cancer (RR‐PTC) urgently needs to be improved and the aberrant trimethylation of histone H3 lysine 27 (H3K27) plays a vital role in BRAFV600E‐MAPK‐induced cancer dedifferentiation and drug resistance. Therefore, dual inhibition of MAPK and histone methyltransferase (EZH2) may produce more favourable treatment effects. In this study, BRAFV600E‐mutant (BCPAP and K1) and BRAF‐wild‐type (TPC‐1) PTC cells were treated with MAPKi (dabrafenib or selumetinib) or EZH2 inhibitor (tazemetostat), or in combination, and the expression of iodine‐metabolizing genes, radioiodine uptake, and toxicity were tested. We found that tazemetostat alone slightly increased iodine‐metabolizing gene expression and promoted radioiodine uptake and toxicity, irrespective of the BRAF status. However, MAPKi induced these effects preferentially in BRAFV600E mutant cells, which was robustly strengthened by tazemetostat incorporation. Mechanically, MAPKi‐induced decrease of trimethylation of H3K27 was evidently intensified by tazemetostat in BRAFV600E‐mutant cells. In conclusion, tazemetostat combined with MAPKi enhances differentiation of PTC cells harbouring BRAFV600E through synergistically decreasing global trimethylation of H3K27, representing a novel differentiation strategy.

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Regulatory roles of insulin growth factor binding protein family in neuroblastoma cell proliferation and differentiation: Potential prognostic biomarkers and therapeutic targets for neuroblastoma

Huang,

Yang,

et al. 2024

Pediatric Discovery

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Neuroblastoma (NB), as a representative of tumors of embryonic origin in children, has specific clinical features. On the one hand, a very small number of NBs may appear to regress on their own. On the other hand, highly malignant NBs can invade the surrounding blood vessels and organs and metastasize to distant bone, bone marrow, and lymph nodes in the early stages of the disease. Based on differential affinities to insulin growth factors (IGFs), insulin growth factor binding proteins (IGFBPs) are classified into two groups: IGF binding proteins (IGFBP1‐6) with high‐affinity and IGF low‐affinity binding proteins, such as IGFBP‐related proteins (IGFBP rP1‐10). IGFBP are crucial regulators of the bioavailability and function of IGF in metabolic signaling and as modulators of IGF signaling, and their role in NB is gaining increasing attention. In this study, we investigate the involvement of IGFBP family members in the growth and differentiation of NB cells, as well as the potential of IGFBPs as prognostic biomarkers and therapeutic targets for human NB.

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EZH2 regulates neuroblastoma cell differentiation via NTRK1 promoter epigenetic modifications

Cited by 62 publications

References 47 publications

Single-cell RNA-sequencing of peripheral neuroblastic tumors reveals an aggressive transitional cell state at the junction of an adrenergic-mesenchymal transdifferentiation trajectory

Single-cell RNA-sequencing of peripheral neuroblastic tumors reveals an aggressive transitional cell state at the junction of an adrenergic-mesenchymal transdifferentiation trajectory

Combined tazemetostat and MAPKi enhances differentiation of papillary thyroid cancer cells harbouring BRAF^V600E by synergistically decreasing global trimethylation of H3K27

Regulatory roles of insulin growth factor binding protein family in neuroblastoma cell proliferation and differentiation: Potential prognostic biomarkers and therapeutic targets for neuroblastoma

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EZH2 regulates neuroblastoma cell differentiation via NTRK1 promoter epigenetic modifications

Cited by 62 publications

References 47 publications

Single-cell RNA-sequencing of peripheral neuroblastic tumors reveals an aggressive transitional cell state at the junction of an adrenergic-mesenchymal transdifferentiation trajectory

Single-cell RNA-sequencing of peripheral neuroblastic tumors reveals an aggressive transitional cell state at the junction of an adrenergic-mesenchymal transdifferentiation trajectory

Combined tazemetostat and MAPKi enhances differentiation of papillary thyroid cancer cells harbouring BRAFV600E by synergistically decreasing global trimethylation of H3K27

Regulatory roles of insulin growth factor binding protein family in neuroblastoma cell proliferation and differentiation: Potential prognostic biomarkers and therapeutic targets for neuroblastoma

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Combined tazemetostat and MAPKi enhances differentiation of papillary thyroid cancer cells harbouring BRAF^V600E by synergistically decreasing global trimethylation of H3K27