Dataset Information

NDRG1 in Cancer: A Suppressor, Promoter, or Both?

ABSTRACT: N-myc downregulated gene-1 (NDRG1) has been variably reported as a metastasis suppressor, a biomarker of poor outcome, and a facilitator of disease progression in a range of different cancers. NDRG1 is poorly understood in cancer due to its context-dependent and pleiotropic functions. Within breast cancer, NDRG1 is reported to be either a facilitator of, or an inhibitor of tumour progression and metastasis. The wide array of roles played by NDRG1 are dependent on post-translational modifications and subcellular localization, as well as the cellular context, for example, cancer type. We present an update on NDRG1, and its association with hallmarks of cancer such as hypoxia, its interaction with oncogenic proteins such as p53 as well its role in oncogenic and metastasis pathways in breast and other cancers. We further comment on its functional implications as a metastasis suppressor and promoter, its clinical relevance, and discuss its therapeutic targetability in different cancers.

SUBMITTER: Joshi V

PROVIDER: S-EPMC9737586 | biostudies-literature | 2022 Nov

REPOSITORIES: biostudies-literature

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NDRG1 in Cancer: A Suppressor, Promoter, or Both?

Joshi Vaibhavi V Lakhani Sunil R SR McCart Reed Amy E AE

Cancers 20221122 23

N-myc downregulated gene-1 (NDRG1) has been variably reported as a metastasis suppressor, a biomarker of poor outcome, and a facilitator of disease progression in a range of different cancers. NDRG1 is poorly understood in cancer due to its context-dependent and pleiotropic functions. Within breast cancer, NDRG1 is reported to be either a facilitator of, or an inhibitor of tumour progression and metastasis. The wide array of roles played by NDRG1 are dependent on post-translational modifications ...[more]

PMID: 36497221

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Project description:Experimental and clinical evidence suggests that N-myc downregulated gene 1 (NDRG1) functions as a suppressor of prostate cancer metastasis. Elucidating pathways that drive survival and invasiveness of NDRG1-deficient prostate cancer cells can help in designing therapeutics to target metastatic prostate cancer cells. However, the molecular mechanisms that lead NDRG1-deficient prostate cancer cells to increased invasiveness remain largely unknown. In this study, we demonstrate that NDRG1-deficient prostate tumors have decreased integrin expression and reduced cell adhesion and motility. Our data indicate that loss of NDRG1 differentially affects Rho GTPases. Specifically, there is a downregulation of active RhoA and Rac1 GTPases with a concomitant upregulation of active Cdc42 in NDRG1-deficient cells. Live cell imaging using a fluorescent sensor that binds to polymerized actin revealed that NDRG1-deficient cells have restricted actin dynamics, thereby affecting cell migration. These cellular and molecular characteristics are in sharp contrast to what is expected after loss of a metastasis suppressor. We further demonstrate that NDRG1-deficient cells have increased resistance to anoikis and increased invasiveness which is independent of its elevated Cdc42 activity. Furthermore, NDRG1 regulates expression and glycosylation of EMMPRIN, a master regulator of matrix metalloproteases. NDRG1 deficiency leads to an increase in EMMPRIN expression with a concomitant increase in matrix metalloproteases and thus invadopodial activity. Using a three-dimensional invasion assay and an in vivo metastasis assay for human prostate xenografts, we demonstrate that NDRG1-deficient prostate cancer cells exhibit a collective invasion phenotype and are highly invasive. Thus, our findings provide novel insights suggesting that loss of NDRG1 leads to a decrease in actin-mediated cellular motility but an increase in cellular invasion, resulting in increased tumor dissemination which positively impacts metastatic outcome.

Project description:Cervical cancer is the most fourth common cancer in women worldwide. The E6 and E7 high-risk human papillomavirus (HPV) types are the main cause of this cancer. Several studies have revealed that promoter methylation of tumor suppressor genes is induced by HPV E7. Recently, it was found that HPV16-E7 and the DNA methyltransferase 1 complex could bind at the cyclin A1 (CCNA1) promoter, resulting in CCNA1 promoter methylation. Therefore, there is a need to study other tumor suppressor genes for which HPV may induce promoter methylation. The present study investigated whether HPV induced cell adhesion molecule 1 (CADM1) and death associated protein kinase 1 (DAPK1) promoter methylation. C33a (no HPV infection) and SiHa (HPV 16 infection) cell lines were used for methylation status and expression observation. It was found that CADM1 and DAPK1 promoter methylation, no expression of CADM1 and decreased expression of DAPK1, was presented in SiHa cells. While no promoter methylation of these two genes was observed in C33a cells, with positive expression of the genes. It was subsequently investigated whether E6 and/or E7 could induce promoter methylation and decrease the expression of these two genes. Methylation-specific primer PCR and quantitative PCR were performed to elucidate the promoter methylation status and expression of CADM1 and DAPK1 in C33a cells transfected with HPV16 E6-PCDNA3 or HPV16 E7-PCDNA3.1 myc-his, compared to empty vector-transfected cells. The results showed that HPV E7 could induce CADM1 promoter methylation and decrease the gene expression in HPV E7 transfected C33a cells, while HPV E6 could induce DAPK1 promoter methylation and decrease its expression in C33a cells transfected with HPV E6. Finally, the mechanism by which HPV E7 induced CADM1 promoter methylation was observed by performing chromatin immunoprecipitation; the data showed that E7 induced CADM1 methylation by the same mechanism as that for CCNA1, by binding at the CADM1 promoter, resulting in the subsequent reduction of its expression in cervical cancer.

Dataset Information

NDRG1 in Cancer: A Suppressor, Promoter, or Both?

Publications

NDRG1 in Cancer: A Suppressor, Promoter, or Both?

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