Abstract
Tumor metastasis remains an obstacle in cancer treatment and is responsible for most cancer-related deaths. Nm23-H1 is one of the first metastasis suppressor proteins discovered with the ability to inhibit metastasis of many cancers including breast, colon, and liver cancer. Although loss of Nm23-H1 is observed in aggressive cancers and correlated with metastatic potential, little is known regarding the mechanisms that regulate its cellular level. Here, we examined the mechanisms that control Nm23-H1 expression in breast cancer cells. Initial studies in aggressive MDA-MB-231 cells (expressing low Nm23-H1) and less invasive MCF-7 cells (expressing high Nm23-H1) revealed that mRNA levels correlated with protein expression, suggesting that transcriptional mechanisms may control Nm23-H1 expression. Truncational analysis of the Nm23-H1 promoter revealed a proximal and minimal promoter that harbor putative binding sites for transcription factors including CTCF and EGR1. CTCF and EGR1 induced Nm23-H1 expression and reduced cell migration of MDA-MB-231 cells. Moreover, CTCF and EGR1 were recruited to the Nm23-H1 promoter in MCF-7 cells and their expression correlated with Nm23-H1 levels. This study indicates that loss of Nm23-H1 in aggressive breast cancer is apparently caused by downregulation of CTCF and EGR1, which potentially drive Nm23-H1 expression to promote a less invasive phenotype.
Highlights
Tumor metastasis remains an obstacle in cancer treatment and is responsible for most cancer-related deaths
Transcript levels of Nm23-H1 were observed to correspond to protein expression levels (Fig. 1b), suggesting that transcriptional mechanisms may be responsible for the loss of Nm23-H1
Putative binding sites for E74-like factor 5 (ELF5) and PU.[1] are present in less active regions upstream of the proximal promoter according to bioinformatic tools. These results suggest that CTCF and EGR1 are recruited to the NME1 promoter to drive Nm23-H1 expression in breast cancer cells
Summary
Tumor metastasis remains an obstacle in cancer treatment and is responsible for most cancer-related deaths. This study indicates that loss of Nm23-H1 in aggressive breast cancer is apparently caused by downregulation of CTCF and EGR1, which potentially drive Nm23-H1 expression to promote a less invasive phenotype. Human cohort studies have revealed a strong correlation between reduced Nm23-H1 protein levels and high metastatic potential in breast, colorectal, gastric, liver, melanoma, and prostate c ancers[5]. Further clinical data indicate a negative correlation between metastatic potential and Nm23-H1 expression at both the transcript and protein levels in breast c ancer[19,20], suggesting that transcriptional mechanisms is a major contributor to the downregulation of Nm23-H1 in aggressive breast cancer. Alternative mechanisms regulating Nm23-H1 protein expression include cathepsin-induced degradation pathways[21] and the action of miRNAs22,23, but these would not contribute to the reduction of transcript levels as observed in metastatic breast cancers
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