MiR-7, Inhibited Indirectly by LincRNA HOTAIR, Directly Inhibits SETDB1 and Reverses the EMT of Breast Cancer Stem Cells by Downregulating the STAT3 Pathway

Abstract

Epithelial-mesenchymal transition (EMT) contributes to tumor invasion and metastasis in many cancers and correlates highly with the acquisition of cancer stem cell (CSC) characteristics. EMT also correlates with changes in specific microRNAs (miRNAs) that have already been integrated into tumorigenic programs as either oncogenes or tumor suppressor genes. Here, we show that miR-7, which was downregulated in breast CSCs (BCSCs) isolated from the human MCF-7 and MDA-MB-231 cell lines, inhibited cell invasion and metastasis, decreased the BCSC population and partially reversed EMT in MDA-MB-231 cells by directly targeting the oncogene, SETDB1. The conspicuous epigenetic transition induced by miR-7 overexpression was found not only in MDA-MB-231 cells but also in BCSC xenograft tumors. MiR-7 inhibited the metastasis of BCSCs in lungs, kidneys, and adrenal glands of NOD/SCID mice. ChIP-polymerase chain reaction result suggested that the SETDB1 induced STAT3 expression by binding to the promoter of STAT3. MiR-7-mediated downregulation of SETDB1 resulted in the suppression of STAT3, which led to the downregulation of c-myc, twist, and mir-9. In addition, the downregulation of miR-7 in BCSCs may be indirectly attributed to lincRNA HOTAIR by modulating the expression of HoxD10 that promotes the expression of miR-7. These findings demonstrate that miR-7 was a tumor suppressor and that the overexpression of miR-7 might serve as a good strategy for treating highly invasive breast cancer.

Epigenetic regulation in human melanoma: past and future

“…HOTAIR suppresses expression of HOXD which produces miR-7, which inhibits expression of the histone methyltransferase SETDB1, required for STAT3 transcription. 83 A corroborating report indicates that SETDB1 is recurrently amplified in melanoma and accelerates tumor development in zebrafish melanoma models harboring the common BRAF V600E mutation. 84 Reports of pro-metastatic activity in multiple pre-clinical model systems, support the hypothesis that this lncRNA is a potential target for melanoma metastasis therapy.…”

Investigation of the Association of HOTAIR Single Nucleotide Polymorphisms and Risk of Breast Cancer in an Iranian Population

“…In addition, HOTAIR has been demonstrated to regulate expression of many oncogenes (HER2, MMP3/9), tumor suppressor genes (PTEN and P21), and key signaling pathways (PI3K/AKT/S6/mTOR, STAT3, and wnt/b-catenin) all of which implicated in cancer development and progression (11). Further supports for the role of HOTAIR in cancer development has originated from a study which has shown that HOTAIR could indirectly downregulate Mir-7 expression and consequently promotes epithelial-mesenchymal transition (EMT) and contributes to tumor invasion and metastasis in breast cancer cell lines (15). Accordingly, evaluation of association of functional polymorphisms within this gene with cancer risk is of practical significance.…”

Quantitative proteomic study of human prostate cancer cells with different metastatic potentials

“…Another study found that SETDB1 positively stimulated the WNT/β-catenin pathway and decreased P53 expression, resulting in enhanced non-small cell lung cancer growth in vitro and in vivo (44). Some authors have shown that miR-7, which is downregulated in the breast cancer MCF-7 and MDA-MB-231 cell lines, inhibited cell invasion and metastasis, decreased the breast cancer stem cell population, and partially reversed the epithelial-mesenchymal transition in MDA-MB-231 cells by directly targeting SETDB1 (45). In addition, SETDB1 is a candidate gene for melanoma susceptibility (46).…”