BMB Reports

Korean Society for Biochemistry and Molecular Biology (생화학분자생물학회)
권호 표지
DOI QR코드

DOI QR Code

Hypermethylation-mediated silencing of NDRG4 promotes pancreatic ductal adenocarcinoma by regulating mitochondrial function

  • Shi, Hao-Hong (Department of Anesthesia, Children's Hospital of Fudan University) ;
  • Liu, Hai-E (Department of Anesthesia, Children's Hospital of Fudan University) ;
  • Luo, Xing-Jing (Department of Anesthesia, Children's Hospital of Fudan University)
  • Received : 2020.08.05
  • Accepted : 2020.10.13
  • Published : 2020.12.31
Download PDF
⟨ Previous Next ⟩

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.

Keywords

References

  1. Kamisawa T, Wood LD, Itoi T and Takaori K (2016) Pancreatic cancer. Lancet 388, 73-85 https://doi.org/10.1016/S0140-6736(16)00141-0
  2. Wolfgang CL, Herman JM, Laheru DA et al (2013) Recent progress in pancreatic cancer. CA Cancer J Clin 63, 318-348 https://doi.org/10.3322/caac.21190
  3. Miller KD, Siegel RL, Lin CC et al (2016) Cancer treatment and survivorship statistics, 2016. CA Cancer J Clin 66, 271-289 https://doi.org/10.3322/caac.21349
  4. Chen W, Zheng R, Baade PD et al (2016) Cancer statistics in China, 2015. CA Cancer J Clin 66, 115-132 https://doi.org/10.3322/caac.21338
  5. Zhou RH, Kokame K, Tsukamoto Y, Yutani C, Kato H and Miyata T (2001) Characterization of the human NDRG gene family: a newly identified member, NDRG4, is specifically expressed in brain and heart. Genomics 73, 86-97 https://doi.org/10.1006/geno.2000.6496
  6. Melotte V, Qu X, Ongenaert M et al (2010) The N-myc downstream regulated gene (NDRG) family: diverse functions, multiple applications. FASEB J 24, 4153-4166 https://doi.org/10.1096/fj.09-151464
  7. Okuda T, Kokame K and Miyata T (2008) Differential expression patterns of NDRG family proteins in the central nervous system. J Histochem Cytochem 56, 175-182 https://doi.org/10.1369/jhc.7A7323.2007
  8. Ohki T, Hongo S, Nakada N, Maeda A and Takeda M (2002) Inhibition of neurite outgrowth by reduced level of NDRG4 protein in antisense transfected PC12 cells. Brain Res Dev Brain Res 135, 55-63 https://doi.org/10.1016/S0165-3806(02)00300-0
  9. Qu X, Jia H, Garrity DM et al (2008) Ndrg4 is required for normal myocyte proliferation during early cardiac development in zebrafish. Dev Biol 317, 486-496 https://doi.org/10.1016/j.ydbio.2008.02.044
  10. Fontenas L, De Santis F, Di Donato V, Degerny C and Chambraud B (2016) Neuronal Ndrg4 is essential for nodes of Ranvier organization in zebrafish. PLoS Genet 12, e1006459 https://doi.org/10.1371/journal.pgen.1006459
  11. Dupays L, Kotecha S, Angst B and Mohun TJ (2009) Tbx2 misexpression impairs deployment of second heart field derived progenitor cells to the arterial pole of the embryonic heart. Dev Biol 333, 121-131 https://doi.org/10.1016/j.ydbio.2009.06.025
  12. Schilling SH, Hjelmeland AB, Radiloff DR et al (2009) NDRG4 is required for cell cycle progression and survival in glioblastoma cells. J Biol Chem 284, 25160-25169 https://doi.org/10.1074/jbc.m109.012484
  13. Kotipatruni RP, Ren X, Thotala D and Jaboin JJ (2015) NDRG4 is a novel oncogenic protein and p53 associated regulator of apoptosis in malignant meningioma cells. Oncotarget 6, 17594-17604 https://doi.org/10.18632/oncotarget.4009
  14. Zhang Z, She J, Yang J et al (2018) NDRG4 in gastric cancer determines tumor cell proliferation and clinical outcome. Mol Carcinog 57, 762-771 https://doi.org/10.1002/mc.22798
  15. Jandrey EHF, Moura RP, Andrade LNS et al (2019) NDRG4 promoter hypermethylation is a mechanistic biomarker associated with metastatic progression in breast cancer patients. NPJ Breast Cancer 5, 11 https://doi.org/10.1038/s41523-019-0106-x
  16. Chu D, Zhang Z, Zhou Y et al (2015) NDRG4, a novel candidate tumor suppressor, is a predictor of overall survival of colorectal cancer patients. Oncotarget 6, 7584-7596 https://doi.org/10.18632/oncotarget.3170
  17. Chen X, Yang Y, Liu J et al (2017) NDRG4 hypermethylation is a potential biomarker for diagnosis and prognosis of gastric cancer in Chinese population. Oncotarget 8, 8105-8119 https://doi.org/10.18632/oncotarget.14099
  18. Melotte V, Lentjes MH, van den Bosch SM et al (2009) N-Myc downstream-regulated gene 4 (NDRG4): a candidate tumor suppressor gene and potential biomarker for colorectal cancer. J Natl Cancer Inst 101, 916-927 https://doi.org/10.1093/jnci/djp131
  19. Okugawa Y, Grady WM and Goel A (2015) Epigenetic alterations in colorectal cancer: emerging biomarkers. Gastroenterology 149, 1204-1225.e1212 https://doi.org/10.1053/j.gastro.2015.07.011
  20. Tahara T and Arisawa T (2015) DNA methylation as a molecular biomarker in gastric cancer. Epigenomics 7, 475-486 https://doi.org/10.2217/epi.15.4
  21. Zheng YZ, Wen J, Cao X et al (2015) 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, 713- 719 https://doi.org/10.3892/mco.2015.511
  22. Liu B and Pilarsky C (2018) Analysis of DNA hypermethylation in pancreatic cancer using methylation-specific PCR and bisulfite sequencing. Methods Mol Biol 1856, 269-282 https://doi.org/10.1007/978-1-4939-8751-1_16
  23. Ahlquist DA, Zou H, Domanico M et al (2012) Next-generation stool DNA test accurately detects colorectal cancer and large adenomas. Gastroenterology 142, 248-256; quiz e225-246 https://doi.org/10.1053/j.gastro.2011.10.031
  24. Imperiale TF, Ransohoff DF, Itzkowitz SH et al (2014) Multitarget stool DNA testing for colorectal-cancer screening. N Engl J Med 370, 1287-1297 https://doi.org/10.1056/NEJMoa1311194
  25. Trotta AP and Chipuk JE (2017) Mitochondrial dynamics as regulators of cancer biology. Cell Mol Life Sci 74, 1999-2017 https://doi.org/10.1007/s00018-016-2451-3
  26. Youle RJ and van der Bliek AM (2012) Mitochondrial fission, fusion, and stress. Science 337, 1062-1065 https://doi.org/10.1126/science.1219855
  27. Pradhan RK, Qi F, Beard DA and Dash RK (2010) Characterization of membrane potential dependency of mitochondrial Ca2+ uptake by an improved biophysical model of mitochondrial Ca2+ uniporter. PLoS One 5, e13278 https://doi.org/10.1371/journal.pone.0013278
  28. Xie KF, Guo DD and Luo XJ (2019) SMDT1-driven change in mitochondrial dynamics mediate cell apoptosis in PDAC. Biochem Biophys Res Commun 511, 323-329 https://doi.org/10.1016/j.bbrc.2019.02.043
  29. Chakraborty PK, Mustafi SB, Xiong X et al (2017) MICU1 drives glycolysis and chemoresistance in ovarian cancer. Nat Commun 8, 14634 https://doi.org/10.1038/ncomms14634
  30. Bustin SA, Benes V, Garson JA et al (2009) The MIQE guidelines: minimum information for publication of quantitative real-time PCR experiments. Clin Chem 55, 611-622 https://doi.org/10.1373/clinchem.2008.112797
  31. Fu Y, Feng MX, Yu J et al (2014) DNA methylation-mediated silencing of matricellular protein dermatopontin promotes hepatocellular carcinoma metastasis by α3β1 integrin-Rho GTPase signaling. Oncotarget 5, 6701-6715 https://doi.org/10.18632/oncotarget.2239