The Ribonucleic Complex HuR-MALAT1 Represses CD133 Expression and Suppresses Epithelial–Mesenchymal Transition in Breast Cancer

Abstract

Epithelial-to-mesenchymal transition (EMT) is a core process underlying cell movement during embryonic development and morphogenesis. Cancer cells hijack this developmental program to execute a multi-step cascade, leading to tumorigenesis and metastasis. CD133 (PROM1), a marker of cancer stem cells, has been shown to facilitate EMT in various cancers, but the regulatory networks controlling CD133 gene expression and function in cancer remain incompletely delineated. In this study, we show that a ribonucleoprotein complex including the long noncoding RNA MALAT1 and the RNA-binding protein HuR (ELAVL1) binds the CD133 promoter region to regulate its expression. In luminal nonmetastatic MCF-7 breast cancer cells, HuR silencing was sufficient to upregulate N-cadherin (CDH2) and CD133 along with a migratory and mesenchymal-like phenotype. Furthermore, we found that in the basal-like metastatic cell line MDA-MB-231 and primary triple-negative breast cancer tumor cells, the repressor complex was absent from the CD133-regulatory region, but was present in the MCF-7 and primary ERþ tumor cells. The absence of the complex from basal-like cells was attributed to diminished expression of MALAT1, which, when overexpressed, dampened CD133 levels. In conclusion, our findings suggest that the failure of a repressive complex to form or stabilize in breast cancer promotes CD133 upregulation and an EMT-like program, providing new mechanistic insights underlying the control of prometastatic processes.Cancer Res; 76(9); 2626-36. Ó2016 AACR.

Emerging roles of long non‐coding RNA in cancer

“…Depletion of MALAT1 in breast cancer ER‐positive luminal cells showed a reduction in cell proliferation, demonstrating its involvement in tumor progression . The chromatin‐associated HuR/MALAT1 functional complex controls CD133 gene expression during the dedifferentiation process of breast cancer cells, both in vitro and in vivo . In the most representative form of ovarian cancer, epithelial ovarian cancer (EOC), MALAT1 induces an epithelial‐to‐mesenchymal transition (EMT) switch via the PI3K/AKT pathway .…”

Dysregulation of long non-coding RNA in breast cancer: an overview of mechanism and clinical implication

“…CD133 is a marker for cancer stem cells and promote the EMT-program in various cancers. Its superior level in TNBC than in ER positive breast subtype, indicates that MALAT1 is more highly expressed in ER positive cell lines [47]. This ER-related expression has been supported both in full-length MALAT1 and an alternatively spliced variant of MALAT1 [48, 49].…”

Missing Links in Epithelial-Mesenchymal Transition: Long Non-Coding RNAs Enter the Arena

“…EMT can be exploited by normal or HuR, MALAT1 binds the CD133 promoter region to repress its expression and suppresses EMT in breast cancer (Fig. 2b, ii) [33]. Thus, further studies are necessary to understand the precise role of MALAT1 in EMT and metastasis and the molecular determinants of its function.…”