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The transcriptional landscape of lncRNAs reveals the oncogenic function of LINC00511 in ER-negative breast cancer.

ABSTRACT: Advances in the molecular characteristics of cancers have facilitated the classification system from morphology to molecular characteristic-based subtypes. Cancer profiling has expanded in its focus from protein-coding genes to noncoding RNAs, with advances in the depth and quality of transcriptome sequencing. Here, we examined the profiles of long noncoding RNAs (lncRNAs) according to breast cancer subtype categories in The Cancer Genome Atlas (TCGA) database to identify a cohort of breast cancer- and oestrogen receptor (ER)-negative-associated lncRNAs. According to the prioritization of variation in ER-negative-associated lncRNAs, we identified and investigated the role of LINC00511 in breast cancer. We determined that high LINC00511 expression was an unfavourable prognostic factor for patients with breast cancer. Furthermore, LINC00511 promoted tumour growth by accelerating the G1/S transition and inhibiting apoptosis. At the transcriptional level, ER deficiency directly affected the expression of LINC00511 activated by transcription factor AP-2 (TFAP-2) in breast cancer cells. Moreover, mechanistic investigations demonstrated that ER-negative-associated LINC00511 interacted with enhancer of zeste homologue 2 (EZH2, the catalytic subunit of polycomb repressive complex 2, PRC2) and recruited PRC2 to mediate histone methylation, contributing to the repression of CDKN1B in the nucleus. This process resulted in altered ER-negative breast cancer cell biology. By highlighting the oncogenic function of LINC00511, we revealed the role of lncRNAs in regulating the network of cell cycle control in ER-negative breast cancer and suggested the exploitation of LINC00511 as an anticancer therapy in the future.

SUBMITTER: Zhang J

PROVIDER: S-EPMC6687715 | biostudies-literature | 2019 Aug

REPOSITORIES: biostudies-literature

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The transcriptional landscape of lncRNAs reveals the oncogenic function of LINC00511 in ER-negative breast cancer.

Zhang Jian J Sui Shiyao S Wu Hao H Zhang Jinfeng J Zhang Xingda X Xu Shouping S Pang Da D

Cell death & disease 20190808 8

Advances in the molecular characteristics of cancers have facilitated the classification system from morphology to molecular characteristic-based subtypes. Cancer profiling has expanded in its focus from protein-coding genes to noncoding RNAs, with advances in the depth and quality of transcriptome sequencing. Here, we examined the profiles of long noncoding RNAs (lncRNAs) according to breast cancer subtype categories in The Cancer Genome Atlas (TCGA) database to identify a cohort of breast canc ...[more]

PMID: 31395854

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Project description:BackgroundIn Iran, the delay in diagnosis and treatment of breast cancer results in low survival rates.AimIt is essential to characterize new therapeutic targets and prognostic breast cancer biomarkers. The rising evidence suggested that long non-coding RNAs (lncRNAs) expression levels are deregulated in human cancers and can use as biomarkers for the rapid diagnosis of breast cancer.MethodsIn the present study, a quantitative real-time polymerase chain reaction (qRT-PCR) technique was used to measure 20 oncogenic and tumor suppressor lncRNAs expression levels in whole blood samples of female breast cancer patients and healthy women. Receiver operating characteristic curve (ROC) was used to assess the diagnostic value of each selected lncRNA as a biomarker.ResultsThe results revealed that some circulating lncRNAs (MEG3, NBAT1, NKILA, GAS5, EPB41L4A-AS2, Z38, and BC040587) were significantly down-regulated in breast cancer patients compared to healthy women. In contrast, other circulating lncRNAs (H19, SPRY4-IT1, XIST, UCA1, AC026904.1, CCAT1, CCAT2, ITGB2-AS, and AK058003) were significantly up-regulated in breast cancer patients compared to controls. It was shown that the expression levels of NKILA, and NBAT1 lncRNAs were related to tumor size, and BC040587 expression level related to age, node metastasis, tumor size, and grade (p < .05). The association between H19 and SPRY4-IT1 lncRNAs with HER-2 was confirmed statistically (p < .05). ROC curves illustrated that the blood levels of SPRY4-IT1, XIST, and H19 lncRNAs have excellent potential in discriminating breast cancer from the healthy controls, showing an AUC of 1.0 (95% CI 1.0-1.0, p = .00), 0.898 (95% CI 0.815-0.981, p = .00), and 0.848 (95% CI 0.701-0.995, p = .01), respectively.ConclusionIn conclusion, the expression levels of circulating H19 and SPRY4-IT1 lncRNAs in breast cancer patients could consider as the prognostic biomarkers and therapeutic targets in breast cancer, because of their excellent power in discriminating breast cancer from healthy individuals and the significant correlation of H19, and SPRY4-IT1 lncRNAs with clinicopathological traits. We also suggest the possible application of BC040587 lncRNA as a diagnostic and prognostic indicator to assess tumor progression in case of verification in larger patients' cohorts.

Project description:The Ets-1 transcription factor is a candidate breast cancer oncogene that regulates the expression of genes involved in tumor progression and metastasis. Ets-1 signaling has also been linked to the development of a basal-like breast cancer phenotype. We recently described a nitric oxide (NO)-induced gene signature that is associated with poor disease outcome in estrogen receptor-negative (ER-) breast cancer and contains both stem cell-like and basal-like components. Thus, we examined the role of Ets-1 in NO signaling and NO-induced phenotypes in ER- human breast cancer cells.Promoter region analyses were performed on genes upregulated in inducible nitric oxide synthase (NOS2) high expressing tumors for Ets-binding sites. In vitro mechanisms were examined in human basal-like breast cancer cells lines. NO signaling effects were studied using either forced NOS2 expression or the use of a chemical NO-donor, diethlylenetriamine NONOate (DETANO).Promoter region analysis of genes that are up-regulated in human ER-negative breast tumors with high NOS2 expression revealed that the Ets-binding sequence is the only common promoter element present in all of these genes, indicating that Ets-1 is the key transcriptional factor down-stream of oncogenic NOS2-signaling. Accordingly, both forced NOS2 over-expression and exposure to NO-donors resulted in significant Ets-1 transcriptional activation in ER- breast cancer cells. Functional studies showed that NO activated Ets-1 transcriptional activity via a Ras/MEK/ERK signaling pathway by a mechanism that involved Ras S-nitrosylation. RNA knock-down of Ets-1 suppressed NO-induced expression of selected basal-like breast cancer markers such as P-cadherin, S100A8, IL-8 and ??-crystallin. Additionally, Ets-1 knock-down reduced NO-mediated cellular proliferation, matrix metalloproteinase and cathepsin B activities, as well as matrigel invasion.These data show that Ets-1 is a key transcriptional mediator of oncogenic NO signaling that promotes the development of an aggressive disease phenotype in ER- breast cancer in an Ets-1 and Ras-dependent manner, providing novel clues of how NOS2 expression in human breast tumors is functionally linked to poor patient survival.

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The transcriptional landscape of lncRNAs reveals the oncogenic function of LINC00511 in ER-negative breast cancer.

Publications

The transcriptional landscape of lncRNAs reveals the oncogenic function of LINC00511 in ER-negative breast cancer.

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