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DNMT Family Induced Down-Regulation of NDRG1 Via DNA Methylation And

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DNMT Family Induced Down-Regulation of NDRG1 Via DNA Methylation And bioRxiv preprint doi: https://doi.org/10.1101/2021.03.01.433329; this version posted March 1, 2021. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY 4.0 International license. 1 DNMT family induced down-regulation of NDRG1 via DNA methylation and 2 clinicopathological significance in gastric cancer 3 Xiaojing Chang1*, Jinguo MA2*, Xiaoying Xue1, Guohui Wang1, Linlin Su1, Xuetao 4 Han1, Huandi Zhou3, Liubing Hou3. 5 1 Department of Radiotherapy, The Second Hospital of Hebei Medical University, 6 Shijiazhuang , China. 7 2 Hulun Buir People’s hospital, Hulun Buir Medical school in nationalities University 8 of inner Mongolia, Hulun Buir, China. 9 3Department of Central Laboratory, The Second Hospital of Hebei Medical 10 University, Shijiazhuang, China 11 *Xiaojing Chang and Jinguo MA have contributed equally to this manuscript. 12 Corresponding author: Xiaoying Xue, MD, PhD, Professor, Department of 13 Radiotherapy, The Second Hospital of Hebei Medical University, NO.215 Heping 14 West Road, Shijiazhuang, China. E-mail:[email protected]. 15 E-mail addresses of authors: 16 Xiaojing Chang: [email protected] 17 Jinguo MA: [email protected] 18 Xiaoying Xue: [email protected]/[email protected] 19 Guohui Wang: [email protected] 20 Linlin Su:[email protected] 21 Xuetao Han :[email protected] 22 Huandi Zhou: [email protected] 23 Liubing Hou: [email protected] 24 Running title: 25 The relationship of DNA methylation of NDRG1and DNMT family in gastric cancer . 26 Funding statement: The authors received funding through the National Natural 27 Science Foundation of Hebei province of China(#H2018206180). 28 Conflict of interest statement: No conflicts of interest are declared by the authors. 29 Ethical approval statement: Our study did not require an ethical board approval 30 because it did not contain human or animal trials. 1 bioRxiv preprint doi: https://doi.org/10.1101/2021.03.01.433329; this version posted March 1, 2021. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY 4.0 International license. 31 DNMT family induced down-regulation of NDRG1 via DNA methylation and 32 clinicopathological significance in gastric cancer 33 Abstract Background Aberrant DNA methylation of tumor suppressor genes is a 34 common event in the development and progression of gastric cancer(GC). Our 35 previous study showed NDRG1, which could suppress cell invasion and migration, 36 was frequently down-regulated by DNA methylation of its promoter in GC. Purpose 37 and Methods To analyze the relationship between the expression and DNA 38 methylation of NDRG1 and DNA methyltransferase (DNMT) family. We performed 39 a comprehensive comparison analysis using 407 patients including sequencing 40 analysis data of GC from TCGA. Results NDRG1 was negatively correlative to 41 DNMT1（p =0.03）, DNMT3A（p =0.01）, DNMT3B（p =0.88）, respectively. 42 Whereas, the DNA methylation of NDRG1 was positively correlative to DNMT 43 family(DNMT1 p<0.01, DNMT3A p<0.001 ， DNMT3B p=0.57, respectively). 44 NDRG1 expression was significantly inverse correlated with invasion depth (p 45 =0.023), and DNMT1 was significantly positive correlated with the degree of tumor 46 cell differentiation (p =0.049). DNMT3B was significantly correlated with tumor cell 47 differentiation (p =0.030). However, there was no association between the expression 48 of DNMT3A and clinicopathological features. The univariate analysis showed that 49 NDRG1and DNMTs had no association with prognosis of GC patients. But, 50 multivariate analysis showed DNMT1 was significantly correlated with prognosis of 51 GC patients. Conclusion These data suggest that down-regulation of NDRG1 in 52 gastric cancer is due to DNA methylation of NDRG1 gene promoter via DNMT 2 bioRxiv preprint doi: https://doi.org/10.1101/2021.03.01.433329; this version posted March 1, 2021. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY 4.0 International license. 53 family. The demethylating agent maybe a potential target drug for GC patients. 54 Keywords: Gastric carcinoma, tumor suppressor gene, NDRG1, DNMT, DNA 55 methylation, metastasis 56 Introduction 57 Gastric carcinoma (GC) is one of the most common digestive malignancies 58 worldwide with the third most common cause of cancer-related death1, 2. The poor 59 prognosis and high recurrence rate are mainly due to lymph node metastasis in its 60 early stage. 61 To date, a number of laboratories have shown that the occurrence of GC is usually 62 caused by oncogenes activation and tumor suppressor genes(TSGs) inactivation. 63 TSGs could suppress tumor cells migration and invasion. Studies have shown that the 64 inactivation of most TSGs are related to DNA methylation of CpG, while the 65 silencing of these genes possibly contributes to the development and progression of 66 tumors3-5. There is increasing evidence that aberrant DNA promoter methylation of 67 TSGs is a major event in the development and progression of gastric cance6. Our 68 previous studies showed NDRG1(N-myc downstream-regulated gene 1), a 69 differentiation-related and tumor suppressor gene, which could suppress cancer cells 70 invasion and migration, was frequently down-regulated by DNA methylation of its 71 promoter in GC，but there were not any mutations in NDRG1 cDNA, and also not 72 significant correlation with histone acetylation 7, 8. 73 DNA methylation of CpG islands, which is carried out 74 by DNA methyltransferase (DNMT) enzymes, is the most widely and the best well 75 studied epigenetic modification event, and leads to transcriptional gene silencing9. 76 DNA methyltransferase (DNMT) enzymes include DNMT1, DNMT2, DNMT3A, 77 DNMT3B, and DNMT3L, among which DNMT1(a maintenance DNMT), DNMT3A 78 and DNMT3B(de novo methyltransferases) are the most important10. In the current 79 study, we focused on the relationship between NDRG1 and DNMT family(DNMT1, 80 DNMT3A and DNMT3B) and their clinical significance in GC by analyzing 81 high-throughput data obtained from TCGA. 3 bioRxiv preprint doi: https://doi.org/10.1101/2021.03.01.433329; this version posted March 1, 2021. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY 4.0 International license. 82 Materials and methods 83 The data that we investigated the mRNA expression of NDRG1 and DNMTs, and 84 the DNA methylation of NDRG1 in GC was obtained from the data portal of TCGA 85 （https://portal.gdc.cancer.gov/）, which is a well-known cancer research project that 86 collects and analyzes high-quality tumor samples and makes the related data available 87 to researchers. We obtained the GC data set (March 1st, 2018 updated), which 88 encompasses 407 gastric tumor samples, and of which 338 cases encompasses the 89 data of DNA methylation of NDRG1. Total of 315 cases contain the complete 90 clinicopathological information. 91 Gastric Cells and Culture 92 Human gastric cancer cell lines, SGC7901 and MKN45 were obtained from the 93 Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences (Shanghai, 94 China), and one immortalized normal gastric cell line, GES1 was obtained from the 95 Oncology Institute of China Medical University. Cells were cultured with RPMI 1640 96 (Invitrogen/Gibco, Grand Island, NY, USA) containing 10 % fetal bovine serum 97 (Invitrogen/Gibco) in a humidified atmosphere of 5 % CO2 at 37 C. 98 Protein Isolation and Western Blot 99 Total cellular protein was extracted from cultured cells and western bolt was 100 performed as previous description7. Protein bands were scanned and quantified using 101 densitometric software (Bio-Rad, California, USA). A rabbit monoclonal 102 anti-NDRG1 antibody was at a dilution of 1:1,000 (Cell Signaling Technology, 103 Danvers, MA, USA). DNMT1, DNMT3A and DNMT3B antibody at a dilution of 104 1:500 were purchased from Bioss, Beijing, China. 105 Statistics 106 All statistical analyses were conducted using SPSS 24.0 (Chicago, IL, USA) and R 107 3.6.1 (https://www.r-project. org/). R language and GraphPad Prism 7 (San Diego, 108 CA, USA) were performed to draw plots. X2 test and Fisher’s exact test were used to 109 generate P values, Values with p < 0.05 are considered as statistically significant. 110 Results 4 bioRxiv preprint doi: https://doi.org/10.1101/2021.03.01.433329; this version posted March 1, 2021. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY 4.0 International license. 111 NDRG1 was negatively correlative to DNMT family 112 Total of 407 gastric cancer cases （ 375 was gastric cancer tissues and 32 was 113 nonmalignant gastric tissues ） which included sequencing analysis data were 114 downloaded form TCGA, then we performed a comprehensive comparison analysis 115 about the mRNA expression of NDRG1 and DNMTs and their clinicopathological 116 features. As shown in Figure 1A-C, NDRG1 mRNA expression was negatively 117 correlative to DNMT1（r=-0.1067, p =0.03）, DNMT3A（r=-0.1015, p =0.01）, 118 DNMT3B（r=-0.0069, p =0.88）. Noteworthy, NDRG1 was significantly associated 119 with DNMT1(p =0.03) and DNMT3A （ p =0.01 ） , and DNMT3A showed the 120 strongest association.
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