Landscape of tumor suppressor long noncoding RNAs in breast cancer

Xingda Zhang,Yanbo Chen,Boran Pang,Shouping Xu,Shipeng Ning,Qin Wang,Junqiang Wu

doi:10.1186/s13046-019-1096-0

Abstract

BackgroundThe landscape and biological functions of tumor suppressor long noncoding RNAs in breast cancer are still unknown.MethodsData from whole transcriptome sequencing of 33 breast specimens in the Harbin Medical University Cancer Center cohort and The Cancer Genome Atlas was applied to identify and validate the landscape of tumor suppressor long noncoding RNAs, which was further validated by The Cancer Genome Atlas pancancer data including 33 cancer types and 12,839 patients. Next, the expression model, prognostic roles, potential biological functions and epigenetic regulation of tumor suppressor long noncoding RNAs were investigated and validated in the breast cancer and pancancer cohorts. Finally, EPB41L4A-AS2 was selected to validate our novel finding, and the tumor suppressive roles of EPB41L4A-AS2 in breast cancer were examined.ResultsWe identified and validated the landscape of tumor suppressor long noncoding RNAs in breast cancer. The expression of the identified long noncoding RNAs was downregulated in cancer tissue samples compared with normal tissue samples, and these long noncoding RNAs correlated with a favorable prognosis in breast cancer patients and the patients in the pancancer cohort. Multiple carcinogenesis-associated biological functions were predicted to be regulated negatively by these long noncoding RNAs. Moreover, these long noncoding RNAs were transcriptionally regulated by epigenetic modification, including DNA methylation and histone methylation modification. Finally, EPB41L4A-AS2 inhibited breast cancer cell proliferation, migration and invasion and induced cell apoptosis in vitro. Mechanistically, EPB41L4A-AS2, acting at least in part as a tumor suppressor, upregulated tumor suppressor gene expression. Moreover, ZNF217 recruited EZH2 to the EPB41L4A-AS2 locus and suppressed the expression of EPB41L4A-AS2 by epigenetically increasing H3K27me3 enrichment.ConclusionsThis work enlarges the functional landscape of known long noncoding RNAs in human cancer and provides novel insights into the suppressive roles of these long noncoding RNAs.

Highlights

The landscape and biological functions of tumor suppressor long noncoding RNAs in breast cancer are still unknown
Discovery and validation of the tumor suppressor long noncoding RNA (TSLNR) landscape in breast cancer First, 33 breast tissue samples in the Harbin Medical University Cancer Center (HMUCC) cohort including 15 paired cancer tissue and corresponding adjacent normal tissue samples and 3 completely normal breast tissue samples acquired during mammoplasty, were subjected to whole transcriptome sequencing
The differential expression of long noncoding RNAs (lncRNAs) from breast cancer patients in the The Cancer Genome Atlas (TCGA) portal was investigated in detail (Fig. 1b and Additional file 1: Table S2)

Summary

Introduction

The landscape and biological functions of tumor suppressor long noncoding RNAs in breast cancer are still unknown. Breast cancer, which is the most common cause of death in women, has an incidence of 22.9% among all malignant tumors in women and causes 13.7% of cancer-related deaths among women with tumors [1,2,3]. Among the noncoding RNAs, long noncoding RNAs (lncRNAs) are defined as transcripts with little or no protein-coding capacity that are longer than 200 nucleotides [10, 11]. Li and his colleagues summarized the functional classification and experimental dissection of lncRNAs. LncRNAs participate in multiple biological processes, including histone methylation, gene transcription, protein translation, and posttranslational modification [9]. The comprehensive understanding of lncRNAs in cancer is still incomplete, and the exploration of the specific roles of lncRNAs in cancer is urgently needed

Methods

Results

Discussion

Conclusion