The long non‐coding RNA DANCR regulates the inflammatory phenotype of breast cancer cells and promotes breast cancer progression via EZH2‐dependent suppression of SOCS3 transcription

Abstract

Long non‐coding RNA (lncRNA) is involved in the regulation of tumorigenesis and metastasis. In this study, we focused on the clinical relevance, biological effects, and molecular mechanisms of the lncRNA differentiation antagonizing non‐protein coding RNA (DANCR) in breast cancer. We compared the expression of DANCR between breast cancer and normal tissues, and between breast cancer cell lines and normal breast epithelial cells using quantitative real‐time PCR (qRT‐PCR) analysis. By knocking down and overexpressing DANCR, we assessed its significance in regulating viability (MTT assay), migration/invasion (Transwell assay), epithelial‐mesenchymal transition (western blot), stemness (mammosphere formation assay and western blot), and production of inflammatory cytokines (qRT‐PCR and ELISA) of breast cancer cells in vitro, as well as xenograft growth in vivo. Furthermore, using ChIP and RNA immunoprecipitation, we examined the reciprocal regulation between DANCR and suppressor of cytokine signaling 3 (SOCS3) in breast cancer. DANCR was significantly up‐regulated in tissue samples from patients with breast cancer, as well as in breast cancer cell lines, as compared with normal tissues and breast epithelial cells, respectively. The highest DANCR expression levels were associated with advanced tumor grades or lymph node metastasis. DANCR was necessary and sufficient to control multiple malignant phenotypes of breast cancer cells in vitro and xenograft growth in vivo. Mechanistically, DANCR promoted the binding of enhancer of zeste homolog 2 (EZH2) to the promoter of SOCS3, thereby epigenetically inhibiting SOCS3 expression. Functionally, SOCS3 up‐regulation or EZH2 inhibition could rescue multiple malignant phenotypes induced by DANCR. Our data indicate that DANCR is a pleiotropic oncogenic lncRNA in breast cancer. Boosting SOCS3 expression may reverse the oncogenic activities of DANCR and thus provide a therapeutic strategy for breast cancer treatment.

The Missing Lnc: The Potential of Targeting Triple-Negative Breast Cancer and Cancer Stem Cells by Inhibiting Long Non-Coding RNAs

“…Notably, MALAT1 regulates Zeb1 expression through miRNA sponging in hepatocellular carcinoma [112]. While DANCR was found to play a role in EMT [93], our analysis of the breast cancer patient tumor data does not reflect that finding. In fact, Zeb1 and Zeb2 are negatively correlated with DANCR expression.…”

“…DANCR expression was correlated with TNM stages, histological grade and lymph node metastasis, and decreased survival in TNBC patients. DANCR knockdown in MDA-MB-231 and MDA-MB-468 cells reduced EMT, stemness, and inflammation [93]. Furthermore, in the normal breast epithelial cell line MCF10A, overexpression of DANCR led to acquisition of EMT, cancer stemness and inflammation properties in the normal cells [93].…”

Long non-coding RNA HAL suppresses the migration and invasion of serous ovarian cancer by inhibiting EMT signaling pathway

“…Recently, it have been shown that lncRNAs are widely involved in various biological processes regulation, including cell cycle, cell differentiation and many other life activities [25,26]. It is found that lncRNA has a great influence on the occurrence and development of liver cancer, laryngeal cancer, lung cancer and gastric cancer.…”

<p>Long Non-Coding Small Nucleolar RNA Host Genes (SNHGs) in Endocrine-Related Cancers</p>

“…62 DANCR may also participate in the enhancer of zeste homolog 2 (EHZ2)-mediated epigenetic repression of the suppressor of cytokine signaling 3 (SOCS3) in breast cancer cells. 63 Sha et al 64 proposed DANCR knockdown was associated with increased binding of EZH2 to the promoters of CD44 and ABCG2 (two triplenegative breast cancer stem cell markers), and the concomitant reduction of expression of these genes decreased cancer cell proliferation and invasion. Furthermore, nanoparticle-mediated RNAi of DANCR was shown to be an effective therapy for triple-negative breast cancer.…”