Downregulation of MEG3 and upregulation of EZH2 cooperatively promote neuroblastoma progression

Neuroblastoma (NB), an embryonic tumour originating from sympathetic crest cells, is the most common extracranial solid tumour type in children with poor overall prognosis. Accumulating evidence has demonstrated the involvement of long non‐coding RNA (lncRNA) in numerous biological processes and the...

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Published in:Journal of cellular and molecular medicine 2022-04, Vol.26 (8), p.2377-2391
Main Authors: Ye, Mujie, Gao, Runnan, Chen, Shiyu, Wei, Meng, Wang, Jing, Zhang, Bowen, Wu, Suwen, Xu, Yuexin, Wu, Peixuan, Chen, Xin, Ma, Jing, Ma, Duan, Dong, Kuiran
Format: Article
Language:English
Subjects:
1-Phosphatidylinositol 3-kinase
AKT protein
Animals
Antibodies
Apoptosis
Autophagy
Biotechnology industry
Cell culture
Cell growth
Cell Line, Tumor
Cell Proliferation - genetics
Children & youth
Correlation analysis
DNMT1 protein
Down-Regulation
Embryogenesis
epigenetics
EZH2
FOXO1 protein
Gene Expression Regulation, Neoplastic
Genes
Histone deacetylase
Immunoprecipitation
long non‐coding RNA
Medical prognosis
MEG3
Membranes
Mesenchyme
Mice
Mice, Nude
Neuroblastoma
Neuroblastoma - pathology
Non-coding RNA
Original
Phosphatidylinositol 3-Kinases - metabolism
Polymerase chain reaction
Proteins
Reagents
RNA, Long Noncoding - genetics
RNA, Long Noncoding - metabolism
Solid tumors
TOR protein
TOR Serine-Threonine Kinases - metabolism
Tumors
Ubiquitination
Up-regulation
Up-Regulation - genetics
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Summary:Neuroblastoma (NB), an embryonic tumour originating from sympathetic crest cells, is the most common extracranial solid tumour type in children with poor overall prognosis. Accumulating evidence has demonstrated the involvement of long non‐coding RNA (lncRNA) in numerous biological processes and their associations with embryonic development and multiple diseases. Ectopic lncRNA expression is linked to malignant tumours. Previous studies by our team indicate that MEG3 attenuates NB autophagy through inhibition of FOXO1 and epithelial‐mesenchymal transition via the mTOR pathway in vitro. Moreover, MEG3 and EZH2 negatively regulate each other. In present study, we first collected 60 NB tissues and 20 adjacent tissues for Quantitative real‐time polymerase chain reaction (Q‐PCR) experiments and performed clinical correlation analysis of the results. At the same time, nude mice were used for subcutaneous tumour formation to detect the effect of MEG3 in vivo. Two NB cell lines, SK‐N‐AS and SK‐N‐BE(2)C, were overexpressed MEG3 and rescued with EZH2 and then were subjected to proliferation, migration, invasion, apoptosis and autophagy experiments. RNA‐binding protein immunoprecipitation (RIP) and Co‐Immunoprecipitation (Co‐IP) experiments were performed to explore the molecular mechanism of MEG3 and EZH2 interaction. Q‐PCR revealed that MEG3 expression was negatively correlated with INSS stage and risk grade of NB. Moreover, MEG3 overexpression was associated with inhibition of NB growth in vivo. MEG3 exerted an anti‐cancer effect via stimulatory effects on EZH2 ubiquitination leading to its degradation. Conversely, EZH2 interacted with DNMT1 and HDAC1 to induce silencing of MEG3. The EZH2 inhibitor, DZNep, and HDAC inhibitor, SAHA, displayed synergistic activity against NB. Combined treatment with DZNep and SAHA inhibited proliferation, migration and invasion of NB through suppression of the PI3K/AKT/mTOR/FOXO1 pathway. In conclusion, downregulation of MEG3 and upregulation of EZH2 forms a feedback loop that concertedly promotes the development of NB. Combined blockage of EZH2 and HDAC1 with the appropriate inhibitors may therefore present an effective treatment strategy for NB cases with low MEG3 and high EZH2 expression.
ISSN:1582-1838
1582-4934
DOI:10.1111/jcmm.17258