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Landscape of Tumor Suppressor Long Noncoding Rnas in Breast Cancer Boran Pang1, Qin Wang2, Shipeng Ning2, Junqiang Wu2, Xingda Zhang2, Yanbo Chen2 and Shouping Xu2*

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Landscape of Tumor Suppressor Long Noncoding Rnas in Breast Cancer Boran Pang1, Qin Wang2, Shipeng Ning2, Junqiang Wu2, Xingda Zhang2, Yanbo Chen2 and Shouping Xu2* Pang et al. Journal of Experimental & Clinical Cancer Research (2019) 38:79 https://doi.org/10.1186/s13046-019-1096-0 RESEARCH Open Access Landscape of tumor suppressor long noncoding RNAs in breast cancer Boran Pang1, Qin Wang2, Shipeng Ning2, Junqiang Wu2, Xingda Zhang2, Yanbo Chen2 and Shouping Xu2* Abstract Background: The landscape and biological functions of tumor suppressor long noncoding RNAs in breast cancer are still unknown. Methods: Data 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. Results: We 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. Conclusions: This 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. Keywords: lncRNAs, Prognosis, Tumorigenesis, Breast cancer, EPB41L4A-AS2 Background obstacles to breast cancer treatment arise from the in- Breast cancer, which is the most common cause of death sensitivity of cancer cells due to the overactivation of in women, has an incidence of 22.9% among all malig- oncogenic signaling pathways, suppression of the expres- nant tumors in women and causes 13.7% of sion of tumor suppressor genes or dormancy and subse- cancer-related deaths among women with tumors [1–3]. quent reawakening of residual tumor cells, which may Although different kinds of treatment, such as surgery, be a major problem with current treatment strategies chemotherapy, hormonal therapy, radiotherapy and im- [6–8]. Therefore, proper modulation of the expression of munotherapy, have improved the prognosis of breast oncogenic or tumor suppressor genes is urgently needed cancer patients to some extent, cancer-related death is to bypass the obstacles that appear in traditional breast still the most common cause of death [4, 5]. The main cancer treatment. As 75% of the genome is transcribed into noncoding * Correspondence: [email protected] RNAs, whether noncoding RNAs can serve as regulators 2Department of Breast Surgery, Harbin Medical University Cancer Hospital, Harbin 150040, China in various biological processes has attracted increasing Full list of author information is available at the end of the article © The Author(s). 2019 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Pang et al. Journal of Experimental & Clinical Cancer Research (2019) 38:79 Page 2 of 18 attention [9, 10]. Among the noncoding RNAs, long was selected to validate our novel finding, and its tumor noncoding RNAs (lncRNAs) are defined as transcripts suppressor roles in breast cancer were examined. As ex- with little or no protein-coding capacity that are longer pected, EPB41L4A-AS2 inhibited breast cancer cell pro- than 200 nucleotides [10, 11]. In a recent report, Li and liferation, migration and invasion and induced cell his colleagues summarized the functional classification apoptosis partly via the upregulation of RARRES1 ex- and experimental dissection of lncRNAs. LncRNAs par- pression. In addition to mediating the DNA methylation ticipate in multiple biological processes, including his- regulation of EPB41L4A-AS2, ZNF217 recruited EZH2 tone methylation, gene transcription, protein translation, to the EPB41L4A-AS2 locus and suppressed the expres- and posttranslational modification [9]. Moreover, sion of EPB41L4A-AS2 by epigenetically increasing lncRNAs have been indicated to be associated with di- H3K27me3 enrichment. verse diseases, such as Alzheimer’s disease, infectious diseases, and cancer [11]. However, the comprehensive Materials and methods understanding of lncRNAs in cancer is still incomplete, Clinical sample collection and whole transcriptome and the exploration of the specific roles of lncRNAs in sequencing cancer is urgently needed. At the HMUCC, 33 samples including 15 breast cancer In our previous study, the oncogenic lncRNA land- tissue samples, 15 adjacent normal tissue samples and 3 scape was identified and validated in breast cancer [10]. normal breast tissue samples were obtained from patients Moreover, we also identified an lncRNA, linc00152, who had not received chemotherapy or radiotherapy. The which functions as a tumor propellant in breast cancer protocol conformed to clinical research guidelines and and pan-cancer [11]. In addition, lncRNAs acting as was approved by the research ethics committee of oncogenic drivers have been reported in breast cancer HMUCC. Written informed consent was obtained from and other cancers [12–15]. Lnc-BM functions as a all of the patients who participated in this study. For JAK2-binding lncRNA and promotes breast cancer brain whole transcriptome sequencing, ribosomal RNA was re- metastasis [13]. LNMAT1 has been proven to promote moved using Ribo-Zero™ Gold kits (Epicentre, Wisconsin, lymphatic metastasis via CCL2-dependent macrophage USA). Sequencing libraries were generated according to recruitment [14]. LncGata6 can maintain cell stemness the manufacturer’s recommendations with varied index la- and promote tumorigenesis [15]. In contrast, few beling using the NEBNext® Ultra™ Directional RNA lncRNAs that function as tumor suppressors have been Library Prep Kit for Illumina (New England Biolabs, reported in breast cancer. Of these reported lncRNAs, Ipswich, USA). The libraries were then sequenced on an EPB41L4A-AS2 and EGOT were first reported to sup- Illumina HiSeq 2500 platform, and 100-bp paired-end press proliferation in breast cancer cells [16, 17]. Other reads were generated. The raw sequencing data from this lncRNAs, including GAS5 [18, 19], ZFAS1 [20], XIST study have been deposited in the NCBI Gene Expression [21, 22], and MEG3 [23–25], function as tumor suppres- Omnibus (GEO) database under accession number sors. However, there is no comprehensive report on the GSE71651 (https://www.ncbi.nlm.nih.gov/geo/query/acc. landscape of tumor suppressor long noncoding RNAs cgi?acc = GSE71651s). (TSLNRs) in breast cancer. In this study, we first defined the lncRNAs that are Access and analysis of public data downregulated in cancer tissue, are correlated with fa- The breast cancer and pancancer genome-wide gene vorable prognosis and function as tumor suppressors in profiles were downloaded from TCGA (https://tcga-da- breast cancer as TSLNRs. We identified and validated ta.nci.nih.gov/). All transcripts were normalized by the the comprehensive landscape of TSLNRs in breast can- log2 method. The correlations between genes were cer via whole transcriptome sequencing of the Harbin assessed by Spearman’s correlation coefficients according Medical University Cancer Center (HMUCC) cohort to the protocol described in a previous study [26]. Un- and The Cancer Genome Atlas (TCGA) breast cancer paired Student’s t-tests were used to detect significant and pancancer data. The expression of the TSLNRs was differences among tumors or between tumor and normal downregulated in cancer tissue compared with normal samples. Guilt-by-association analysis was performed to tissue, and the expression of some TSLNRs was nega- identify genes that were positively and negatively corre- tively associated with TNM stage in the pancancer data. lated with lncRNA expression [9, 27, 28]. During this Next, the TSLNRs were found to be correlated with a fa- analysis, the TCGA data were evaluated to generate a vorable prognosis in breast cancer patients and the pa- pairwise Spearman’s correlation between the
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