N-myc downstream regulated gene 1 modulates Wnt-β-catenin signalling and pleiotropically suppresses metastasis.
Bottom Line: Here we demonstrate that the tumour metastasis suppressor gene, NDRG1, interacts with the Wnt receptor, LRP6, followed by blocking of the Wnt signalling, and therefore, orchestrates a cellular network that impairs the metastatic progression of tumour cells.Importantly, restoring NDRG1 expression by a small molecule compound significantly suppressed the capability of otherwise highly metastatic tumour cells to thrive in circulation and distant organs in animal models.In addition, our analysis of clinical cohorts data indicate that Wnt+/NDRG-/LRP+ signature has a strong predictable value for recurrence-free survival of cancer patients.
Affiliation: Department of Medical Microbiology, Southern Illinois University School of Medicine, Springfield, IL, USA.Show MeSH
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Mentions: Previously, we demonstrated that NDRG1 was able to modulate the metastasis-promoting gene ATF3, and therefore, we further explored a possibility that ATF3 expression was regulated by Wnt signalling. We found that Wnt strongly increased the nuclear expression of ATF3 and that the induction of NDRG1 strongly abrogated this effect (Supporting Information Fig S1H). Consistently, ectopic expression of β-catenin and TCF also significantly promoted the expression of ATF3 at both mRNA and protein levels in prostate and breast cancer cells (Fig 2A). Moreover, a deletion of β-catenin/TCF binding consensus sequence of the ATF3 promoter significantly blocked the suppressive effect of NDRG1 (Fig 2B), suggesting that down-regulation of ATF3 by NDRG1 depends directly on the β-catenin/TCF binding site in the ATF3 promoter. In agreement with this result, we found that Wnt treatment led to a significant increase in the ATF3 promoter activity of wild type but not mutant (Fig 2C), and that Wnt substantially augmented the level of ATF3 protein which was decreased upon induced NDRG1 expression (Fig 3B). In addition, our results of ChIP assay by precipitating β-catenin/TCF-chromatin complex clearly showed that β-catenin/TCF binds to the predicted region of ATF3 promoter, while expression of NDRG1 led to more than 95% decrease in binding efficiency (Fig 2D), which provided direct evidence that NDRG1 suppresses ATF3 expression by blocking Wnt-β-catenin signalling.
Affiliation: Department of Medical Microbiology, Southern Illinois University School of Medicine, Springfield, IL, USA.