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Original Article | Open Access

Coordinated silencing of the Sp1-mediated long noncoding RNA MEG3 by EZH2 and HDAC3 as a prognostic factor in pancreatic ductal adenocarcinoma

Ting Han1,*, Meng Zhuo1,*, Cuncun Yuan2, Xiuying Xiao1, Jiujie Cui1, Guangrong Qin3, Liwei Wang1,4 ( ), Feng Jiao1 ( )
Department of Oncology, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai 200127, China
Department of Pathology, Fudan University Eye Ear Nose and Throat Hospital, Shanghai 201114, China
Shanghai Center for Bioinformation Technology, Shanghai 201203, China
State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai 200127, China

*These authors contributed equally to this work.

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Abstract

Objective

Pancreatic ductal adenocarcinoma (PDAC) is a disease with high mortality. Many so-called “junk” noncoding RNAs need to be discovered in PDAC. The purpose of this study was therefore to investigate the function and regulatory mechanism of the long noncoding RNA MEG3 in PDAC.

Methods

The Gene Expression Omnibus database (GEO database) was used to determine the differential expression of long noncoding RNAs in PDAC, and MEG3 was selected for subsequent verification. Tissue and cell samples were used to verify MEG3 expression, followed by functional detection in vitro and in vivo. Microarrays were used to characterize long noncoding RNA and mRNA expression profiles. Competing endogenous RNA analyses were used to detect differential MEG3 and relational miRNA expression in PDAC. Finally, promoter analyses were conducted to explain the downregulation of MEG3 PDAC.

Results

We generated a catalogue of PDAC-associated long noncoding RNAs in the GEO database. The ectopic expression of MEG3 inhibited PDAC growth and metastasis in vitro and in vivo, which was statistically significant (P＜0.05). Microarray analysis showed that multiple microRNAs interacted with MEG3. We also showed that MEG3, as a competing endogenous RNA, directly sponged miR-374a-5p to regulate PTEN expression. The transcription factor, Sp1, recruited EZH2 and HDAC3 to the promoter and transcriptionally repressed MEG3 expression. Finally, clinical data showed that MEG3 and miR-374a-5p expressions were correlated with clinicopathological features. Statistically, Sp1, EZH2, HDAC3, and miR-374a-5p were negatively correlated with MEG3 (P＜0.05).

Conclusions

Reduced MEG3 levels played a crucial role in the PDAC malignant phenotype, which provided insight into novel and effective molecular targets of MEG3 for pancreatic cancer treatment.

Keywords

Pancreatic ductal adenocarcinomaEZH2HDAC3MEG3Sp1miR-374a-5p

Electronic Supplementary Material

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Cancer Biology & Medicine
Volume 17 Issue 4,
November 2020
Pages 953-969
DOI: 10.20892/j.issn.2095-3941.2019.0427
Cite this article:
Han T, Zhuo M, Yuan C, et al. Coordinated silencing of the Sp1-mediated long noncoding RNA MEG3 by EZH2 and HDAC3 as a prognostic factor in pancreatic ductal adenocarcinoma. Cancer Biology & Medicine, 2020, 17(4): 953-969. https://doi.org/10.20892/j.issn.2095-3941.2019.0427

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Received: 27 November 2019
Accepted: 10 July 2020
Published: 15 November 2020
©2020 Cancer Biology & Medicine.

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