Hypermethylation-mediated silencing of NDRG4 promotes pancreatic ductal adenocarcinoma by regulating mitochondrial function
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The N-myc downstream regulated gene (NDRG) family members are dysregulated in several tumors. Functionally, NDRGs play an important role in the malignant progression of cancer cells. However, little is known about the potential implications of NDRG4 in pancreatic ductal adenocarcinoma (PDAC). The aim of the current study was to elucidate the expression pattern of NDRG4 in PDAC and evaluate its potential cellular biological effects. Here, we firstly report that epigenetic-mediated silencing of NDRG4 promotes PDAC by regulating mitochondrial function. Data mining demonstrated that NDRG4 was significantly down-regulated in PDAC tissues and cells. PDAC patients with low NDRG4 expression showed poor prognosis. Epigenetic regulation by DNA methylation was closely associated with NDRG4 down-regulation. NDRG4 overexpression dramatically suppressed PDAC cell growth and metastasis. Further functional analysis demonstrated that up-regulated NDRG4 in SW1990 and Canpan1 cells resulted in attenuated mitochondrial function, including reduced ATP production, decreased mitochondrial membrane potential, and increased fragmented mitochondria. However, opposite results were obtained for HPNE cells with NDRG4 knockdown. These results indicate that hypermethylation-driven silencing of NDRG4 can promote PDAC by regulating mitochondrial function and that NDRG4 could be as a potential biomarker for PDAC patients.
Abstract
The N-myc downstream regulated gene (NDRG) family members are dysregulated in several tumors. Functionally, NDRGs play an important role in the malignant progression of cancer cells. However, little is known about the potential implications of NDRG4 in pancreatic ductal adenocarcinoma (PDAC). The aim of the current study was to elucidate the expression pattern of NDRG4 in PDAC and evaluate its potential cellular biological effects. Here, we firstly report that epigenetic-mediated silencing of NDRG4 promotes PDAC by regulating mitochondrial function. Data mining demonstrated that NDRG4 was significantly down-regulated in PDAC tissues and cells. PDAC patients with low NDRG4 expression showed poor prognosis. Epigenetic regulation by DNA methylation was closely associated with NDRG4 down-regulation. NDRG4 overexpression dramatically suppressed PDAC cell growth and metastasis. Further functional analysis demonstrated that up-regulated NDRG4 in SW1990 and Canpan1 cells resulted in attenuated mitochondrial function, including reduced ATP production, decreased mitochondrial membrane potential, and increased fragmented mitochondria. However, opposite results were obtained for HPNE cells with NDRG4 knockdown. These results indicate that hypermethylation-driven silencing of NDRG4 can promote PDAC by regulating mitochondrial function and that NDRG4 could be as a potential biomarker for PDAC patients.
참고문헌 (31)
- Kamisawa T, "Pancreatic cancer", Lancet, 388, pp.73~85 (2016)
- Wolfgang CL, "Recent progress in pancreatic cancer", CA Cancer J Clin, 63, pp.318~348 (2013)
- Miller KD, "Cancer treatment and survivorship statistics, 2016", CA Cancer J Clin, 66, pp.271~289 (2016)
- Chen W, "Cancer statistics in China, 2015", CA Cancer J Clin, 66, pp.115~132 (2016)
- Zhou RH, "Characterization of the human NDRG gene family : a newly identified member, NDRG4, is specifically expressed in brain and heart", Genomics, 73, pp.86~97 (2001)
- Melotte V, "The N-myc downstream regulated gene(NDRG)family : diverse functions, multiple applications", FASEB J, 24, pp.4153~4166 (2010)
- Okuda T, "Differential expression patterns of NDRG family proteins in the central nervous system", J Histochem Cytochem, 56, pp.175~182 (2008)
- Ohki T, "Inhibition of neurite outgrowth by reduced level of NDRG4 protein in antisense transfected PC12 cells", Brain Res Dev Brain Res, 135, pp.55~63 (2002)
- Qu X, "Ndrg4 is required for normal myocyte proliferation during early cardiac development in zebrafish", Dev Biol, 317, pp.486~496 (2008)
- Fontenas L, "Neuronal Ndrg4 is essential for nodes of Ranvier organization in zebrafish", PLoS Genet, 12, pp.e1006459~ (2016)
- Dupays L, "Tbx2misexpression impairs deployment of second heart field derived progenitor cells to the arterial pole of the embryonic heart", Dev Biol, 333, pp.121~131 (2009)
- Schilling SH, "NDRG4 is required for cell cycle progression and survival in glioblastoma cells", J Biol Chem, 284, pp.25160~25169 (2009)
- Kotipatruni RP, "NDRG4 is a novel oncogenic protein and p53 associated regulator of apoptosis in malignant meningioma cells", Oncotarget, 6, pp.17594~17604 (2015)
- Zhang Z, "NDRG4 in gastric cancer determines tumor cell proliferation and clinical outcome", Mol Carcinog, 57, pp.762~771 (2018)
- Jandrey EHF, "NDRG4promoter hypermethylation is a mechanistic biomarker associated with metastatic progression in breast cancer patients", NPJ Breast Cancer, 5, pp.11~ (2019)
- Chu D, "NDRG4, a novel candidate tumor suppressor, is a predictor of overall survival of colorectal cancer patients", Oncotarget, 6, pp.7584~7596 (2015)
- Chen X, "NDRG4 hypermethylation is a potential biomarker for diagnosis and prognosis of gastric cancer in Chinese population", Oncotarget, 8, pp.8105~8119 (2017)
- Melotte V, "N-Myc downstream-regulated gene 4(NDRG4) : a candidate tumor suppressor gene and potential biomarker for colorectal cancer", J Natl Cancer Inst, 101, pp.916~927 (2009)
- Okugawa Y, "Epigenetic alterations in colorectal cancer : emerging biomarkers", Gastroenterology, 149, pp.1204~1225.e1212 (2015)
- Tahara T, "DNA methylation as a molecular biomarker in gastric cancer", Epigenomics, 7, pp.475~486 (2015)
- Zheng YZ, "Decreased mRNA expression of transcription factor forkhead box F2 is an indicator of poor prognosis in patients with resected esophageal squamous cell carcinoma", Mol Clin Oncol, 3, pp.713~719 (2015)
- Liu B, "Analysis of DNA hypermethylation in pancreatic cancer using methylation-specific PCR and bisulfite sequencing", Methods Mol Biol, 1856, pp.269~282 (2018)
- Ahlquist DA, "Nextgeneration stool DNA test accurately detects colorectal cancer and large adenomas", Gastroenterology, 142, pp.248~256 (2012)
- Imperiale TF, "Multitarget stool DNA testing for colorectal-cancer screening", N Engl J Med, 370, pp.1287~1297 (2014)
- Trotta AP, "Mitochondrial dynamics as regulators of cancer biology", Cell Mol Life Sci, 74, pp.1999~2017 (2017)
- Youle RJ, "Mitochondrial fission, fusion, and stress", Science, 337, pp.1062~1065 (2012)
- Pradhan RK, "Characterization of membrane potential dependency of mitochondrial Ca2+ uptake by an improved biophysical model of mitochondrial Ca2+ uniporter", PLoS One, 5, pp.e13278~ (2010)
- Xie KF, "SMDT1-driven change in mitochondrial dynamics mediate cell apoptosis in PDAC", Biochem Biophys Res Commun, 511, pp.323~329 (2019)
- Chakraborty PK, "MICU1drives glycolysis and chemoresistance in ovarian cancer", Nat Commun, 8, pp.14634~ (2017)
- Bustin SA, "The MIQE guidelines : minimum information for publication of quantitative real-time PCR experiments", Clin Chem, 55, pp.611~622 (2009)
- Fu Y, "DNA methylationmediated silencing of matricellular protein dermatopontin promotes hepatocellular carcinoma metastasis by 3 1integrin-Rho GTPase signaling", Oncotarget, 5, pp.6701~6715 (2014)