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The role of DDX3 in regulating Snail.

ABSTRACT: DDX3, a DEAD box protein family member, appears to promote the progression of some cancers, which may partly result from its impedance of death receptor-mediated apoptosis. We found that another mechanism by which DDX3 may aid cancer progression is by promoting increased levels of the transcription factor Snail. Snail represses expression of cellular adhesion proteins, leading to increased cell migration and metastasis of many types of cancer. Knockdown of DDX3 levels by shRNA reduced basal levels of Snail in HeLa and MCF-7 cells, and this was associated with reduced cell proliferation and migration. Snail protein and mRNA levels were increased by treatment with the HDAC inhibitors sodium butyrate or trichostatin A, and these increases were attenuated in cells with DDX3 knocked down. Treatment of cells with camptothecin was discovered to increase Snail protein levels, and this increase was diminished in cells with DDX3 knocked down. Analysis of 31 patient glioblastoma multiforme (GBM) samples revealed a significant correlation between the levels of DDX3 and Snail. Thus, DDX3 is required for basal Snail expression and increases in Snail induced by HDAC inhibitors or camptothecin, indicating that this action of DDX3 may contribute to its promotion of the progression of some cancers.

SUBMITTER: Sun M

PROVIDER: S-EPMC3046234 | biostudies-literature | 2011 Mar

REPOSITORIES: biostudies-literature

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The role of DDX3 in regulating Snail.

Sun Mianen M Song Ling L Zhou Tong T Gillespie G Yancey GY Jope Richard S RS

Biochimica et biophysica acta 20110112 3

DDX3, a DEAD box protein family member, appears to promote the progression of some cancers, which may partly result from its impedance of death receptor-mediated apoptosis. We found that another mechanism by which DDX3 may aid cancer progression is by promoting increased levels of the transcription factor Snail. Snail represses expression of cellular adhesion proteins, leading to increased cell migration and metastasis of many types of cancer. Knockdown of DDX3 levels by shRNA reduced basal leve ...[more]

PMID: 21237216

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Project description:Purpose We previously found that Hu antigen R (HuR) can regulate the proliferation and metastasis of esophageal cancer cells. This study aims to explore the effects of HuR on the radiosensitivity of esophageal cancer. Materials and Method Analyses of CCK-8, colony formation assay, Western blot, immunofluorescence, flow cytometry, reactive oxygen species (ROS), and mitochondrial membrane potential were conducted to characterize the esophageal cancer cells. Nude mouse models were used to detect the effects of HuR in a combination of X-ray treatment on the subcutaneous xenografts of esophageal cancer. In addition, a luciferase assay was used to detect the direct interaction of HuR with Snail mRNA 3’-UTR. Results The down-regulation of HuR combined with X-ray can significantly inhibit the proliferation and colony formation of esophageal cancer cells. Flow cytometry data showed that the down-regulation of HuR could induce a G1 phase cell cycle block in esophageal cancer cells, and aggravate X-ray-induced apoptosis, indicated by the increases of apoptosis-related proteins Bax, caspase-3 and caspase-9. Moreover, the down-regulation of HuR could significantly impair the mitochondrial membrane potential and increase the ROS production and DNA double-strand break marker γH2AX expression in esophageal cancer cells that were exposed to X-rays. In vivo data showed that the down-regulation of HuR combined with radiation significantly decreased the growth of subcutaneous xenograft tumors. Furthermore, HuR could interact with Snail. Up-regulation of Snail can reverse the EMT inhibitory effects caused by HuR down-regulation, and attenuate the tumor-inhibiting and radiosensitizing effects caused by HuR down-regulation. Conclusion In summary, our data demonstrate that HuR effectively regulates the radiosensitivity of esophageal cancer, which may be achieved by stabilizing Snail. Thus, HuR/Snail axis is a potentially therapeutic target for the treatment of esophageal cancer.

Dataset Information

The role of DDX3 in regulating Snail.

Publications

The role of DDX3 in regulating Snail.

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