N-myc downstream-regulated gene 1 inhibits the proliferation of colorectal cancer through emulative antagonizing NEDD4-mediated ubiquitylation of p21

Abstract

BackgroundN-myc downstream-regulated gene 1 (NDRG1) has been shown to play a key role in tumor metastasis. Recent studies demonstrate that NDRG1 can suppress tumor growth and is related to tumor proliferation; however, the mechanisms underlying these effects remain obscure.MethodsImmunohistochemistry (IHC) was used to detect NDRG1 and p21 protein expression in colorectal cancer tissue, and clinical significance of NDRG1 was also analyzed. CCK-8 assay, colony formation assay, flow cytometry, and xenograft model were used to assess the effect of NDRG1 on tumor proliferation in vivo and in vitro. The mechanisms underlying the effect of NDRG1 were investigated using western blotting, immunofluorescence, immunoprecipitation, and ubiquitylation assay.ResultsNDRG1 was down-regulated in CRC tissues and correlated with tumor size and patient survival. NDRG1 inhibited tumor proliferation through increasing p21 expression via suppressing p21 ubiquitylation. NDRG1 and p21 had a positive correlation both in vivo and in vitro. Mechanistically, E3 ligase NEDD4 could directly interact with and target p21 for degradation. Moreover, NDRG1 could emulatively antagonize NEDD4-mediated ubiquitylation of p21, increasing p21 expression and inhibit tumor proliferation.ConclusionOur study could fulfill potential mechanisms of the NDRG1 during tumorigenesis and metastasis, which may serve as a tumor suppressor and potential target for new therapies in human colorectal cancer.

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“…NEDD4 could target p21 protein for degradation by increasing the ubiquitylation of p21, and promote cell proliferation. N-myc downstream-regulated gene 1 (NDRG1) inhibits colorectal cancer cell proliferation through emulatively antagonizing NEDD4-mediated ubiquitylation of p21, which suggests an oncogenic role of NEDD4 in colorectal cancer ( 14 ). In malignant glioma, researchers found that NEDD4 directly promotes cell migration and invasion, but does not affect the proliferation and apoptosis.…”

Gene Expression Signatures of a Preclinical Mouse Model during Colorectal Cancer Progression under Low-Dose Metronomic Chemotherapy

“…NDRG1 is the most significantly affected gene of the validated candidates. Interestingly, NDRG1 was previously shown to be a metastasis suppressor and is highly downregulated in colorectal cancer [61,62]. Furthermore, we found several regulated genes belonging to the group of the ISGylation pathway, which is important for ISG15 conjugation [64,65].…”

“…NDRG1 is the most significantly affected gene of the validated candidates. Interestingly, NDRG1 was previously shown to be a metastasis suppressor and is highly downregulated in colorectal cancer [ 61 , 62 ].…”

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