Effects of ginsenoside Rg3 on epigenetic modification in ovarian cancer cells

Zhao,Lingqin; Shou,Huafeng; Chen,Lu; Gao,Wen; Fang,Chenyan; Zhang,Ping

doi:10.3892/or.2019.7115

Effects of ginsenoside Rg3 on epigenetic modification in ovarian cancer cells

Authors:
- Lingqin Zhao
- Huafeng Shou
- Lu Chen
- Wen Gao
- Chenyan Fang
- Ping Zhang
View Affiliations

Affiliations: Department of Gynecological Oncology, Zhejiang Cancer Hospital, Hangzhou, Zhejiang 310022, P.R. China, Zhejiang Chinese Medical University, Hangzhou, Zhejiang 310051, P.R. China
Published online on: April 12, 2019 https://doi.org/10.3892/or.2019.7115
Pages: 3209-3218
Copyright: © Zhao et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Epigenetic modifications are closely related to oncogene activation and tumor suppressor gene inactivation. The aim of this study was to determine the effects of ginsenoside Rg3 on epigenetic modification in ovarian cancer cells. Cell proliferation, metastasis, invasion and apoptosis were respectively determined using Cell Counting Kit‑8 (CCK‑8), wound healing, Transwell and flow cytometric assays. Methylation levels were determined using methylation specific PCR (MSP). Related‑factor expression was detected by conducting real‑time‑qPCR (RT‑qPCR) and western blotting. The results revealed that cell proliferation was inhibited by ginsenoside Rg3 (0, 25, 50, 100 and 200 µg/ml) in a time‑dependent manner (12, 24 and 48 h). Ginsenoside Rg3 (50, 100 and 200 µg/ml) was selected to treat cells in various experiments. When ovarian cells were treated with ginsenoside Rg3, cell apoptosis was observed to be promoted, while cell metastasis and invasion were inhibited at 48 h. The results of the present study revealed that in the promoter regions of p53, p16 and hMLH1, the methylation levels decreased, while the mRNA and protein levels significantly increased. The activities of DNMTs and mRNA as well as protein levels of DNMT1, DNMT3a and DNMT3b were decreased by Rg3. The data also demonstrated that the mRNA and protein levels of acetyl‑H3 K14/K9 and acetyl‑H4 K12/K5/K16 were increased by Rg3. Hence, ginsenoside Rg3 inhibited ovarian cancer cell viability, migration and invasion as well as promoted cell apoptosis.

View Figures

View References

1	Henderson JT, Webber EM and Sawaya GF: U.S. preventive services task force evidence syntheses formerly systematic evidence reviews Screening for ovarian cancer: An updated evidence review for the U.S. preventive services task force. Agency for Healthcare Research and Quality (US). Report No.: 17-05231-EF-1. 2018.
2	Woolas RP, Xu FJ, Jacobs IJ, Yu YH, Daly L, Berchuck A, Soper JT, Clarke-Pearson DL, Oram DH and Bast RC Jr: Elevation of multiple serum markers in patients with stage I ovarian cancer. J Natl Cancer Inst. 85:1748–1751. 1993. View Article : Google Scholar : PubMed/NCBI
3	Smith RA, Manassaram-Baptiste D, Brooks D, Doroshenk M, Fedewa S, Saslow D, Brawley OW and Wender R: Cancer screening in the United States, 2015: A review of current American cancer society guidelines and current issues in cancer screening. CA Cancer J Clin. 65:30–54. 2015. View Article : Google Scholar : PubMed/NCBI
4	Rothbart SB and Strahl BD: Interpreting the language of histone and DNA modifications. Biochim Biophys Acta. 1839:627–643. 2014. View Article : Google Scholar : PubMed/NCBI
5	Vinci MC, Polvani G and Pesce M: Epigenetic programming and risk: The birthplace of cardiovascular disease? Stem Cell Rev. 9:241–253. 2013. View Article : Google Scholar : PubMed/NCBI
6	Perlin E and Moquin RB: Serum DNA levels in patients with malignant disease. Am J Clin Pathol. 58:601–602. 1972. View Article : Google Scholar : PubMed/NCBI
7	Ibanez de Caceres I, Battagli C, Esteller M, Herman JG, Dulaimi E, Edelson MI, Bergman C, Ehya H, Eisenberg BL and Cairns P: Tumor cell-specific BRCA1 and RASSF1A hypermethylation in serum, plasma, and peritoneal fluid from ovarian cancer patients. Cancer Res. 64:6476–6481. 2004. View Article : Google Scholar : PubMed/NCBI
8	Gurard-Levin ZA and Almouzni G: Histone modifications and a choice of variant: A language that helps the genome express itself. F1000Prime Rep. 6:762014. View Article : Google Scholar : PubMed/NCBI
9	Hake SB, Xiao A and Allis CD: Linking the epigenetic ‘language’ of covalent histone modifications to cancer. Br J Cancer. 90:761–769. 2004. View Article : Google Scholar : PubMed/NCBI
10	Strahl BD and Allis CD: The language of covalent histone modifications. Nature. 403:41–45. 2000. View Article : Google Scholar : PubMed/NCBI
11	Gillis CN: Panax ginseng pharmacology: A nitric oxide link? Biochem Pharmacol. 54:1–8. 1997. View Article : Google Scholar : PubMed/NCBI
12	Liao B, Newmark H and Zhou R: Neuroprotective effects of ginseng total saponin and ginsenosides Rb1 and Rg1 on spinal cord neurons in vitro. Exp Neurol. 173:224–234. 2002. View Article : Google Scholar : PubMed/NCBI
13	Xu TM, Xin Y, Cui MH, Jiang X and Gu LP: Inhibitory effect of ginsenoside Rg3 combined with cyclophosphamide on growth and angiogenesis of ovarian cancer. Chin Med J. 120:584–588. 2007. View Article : Google Scholar : PubMed/NCBI
14	Wang JH, Nao JF, Zhang M and He P: 20(s)-ginsenoside Rg3 promotes apoptosis in human ovarian cancer HO-8910 cells through PI3K/Akt and XIAP pathways. Tumour Biol. 35:11985–11994. 2014. View Article : Google Scholar : PubMed/NCBI
15	Liu T, Zhao L, Zhang Y, Chen W, Liu D, Hou H, Ding L and Li X: Ginsenoside 20(S)-Rg3 targets HIF-1alpha to block hypoxia-induced epithelial-mesenchymal transition in ovarian cancer cells. PLoS One. 9:e1038872014. View Article : Google Scholar : PubMed/NCBI
16	Liu T, Zhao L, Hou H, Ding L, Chen W and Li X: Ginsenoside 20(S)-Rg3 suppresses ovarian cancer migration via hypoxia-inducible factor 1 alpha and nuclear factor-kappa B signals. Tumour Biol. 39:10104283176922252017.PubMed/NCBI
17	Xu TM, Cui MH, Xin Y, Gu LP, Jiang X, Su MM, Wang DD and Wang WJ: Inhibitory effect of ginsenoside Rg3 on ovarian cancer metastasis. Chin Med J. 121:1394–1397. 2008. View Article : Google Scholar : PubMed/NCBI
18	Zheng X, Chen W, Hou H Li J, Li H, Sun X, Zhao L and Li X: Ginsenoside 20(S)-Rg3 induced autophagy to inhibit migration and invasion of ovarian cancer. Biomed Pharmacother. 85:620–626. 2017. View Article : Google Scholar : PubMed/NCBI
19	Powell CB, Kenley E, Chen LM, Crawford B, McLennan J, Zaloudek C, Komaromy M, Beattie M and Ziegler J: Risk-reducing salpingo-oophorectomy in BRCA mutation carriers: Role of serial sectioning in the detection of occult malignancy. J Clin Oncol. 23:127–132. 2005. View Article : Google Scholar : PubMed/NCBI
20	Lee Y, Miron A, Drapkin R, Nucci MR, Medeiros F, Saleemuddin A, Garber J, Birch C, Mou H, Gordon RW, et al: A candidate precursor to serous carcinoma that originates in the distal fallopian tube. J Pathol. 211:26–35. 2007. View Article : Google Scholar : PubMed/NCBI
21	Sallum LF, Andrade L, Ramalho S, Ferracini AC, de Andrade Natal R, Brito ABC, Sarian LO and Derchain S: WT1, p53 and p16 expression in the diagnosis of low- and high-grade serous ovarian carcinomas and their relation to prognosis. Oncotarget. 9:15818–15827. 2018. View Article : Google Scholar : PubMed/NCBI
22	Heckl M, Schmoeckel E, Hertlein L, Rottmann M, Jeschke U and Mayr D: The ARID1A, p53 and β-Catenin statuses are strong prognosticators in clear cell and endometrioid carcinoma of the ovary and the endometrium. PLoS One. 13:e01928812018. View Article : Google Scholar : PubMed/NCBI
23	Marinas MC, Mogos DG, Simionescu CE, Stepan A and Tanase F: The study of p53 and p16 immunoexpression in serous borderline and malignant ovarian tumors. Rom J Morphol Embryol. 53:1021–1025. 2012.PubMed/NCBI
24	Hu G, Li P, Li Y, Wang T, Gao X, Zhang W and Jia G: Methylation levels of P16 and TP53 that are involved in DNA strand breakage of 16HBE cells treated by hexavalent chromium. Toxicol Lett. 249:15–21. 2016. View Article : Google Scholar : PubMed/NCBI
25	Geraldes C, Goncalves AC, Cortesao E, Pereira MI, Roque A, Paiva A, Ribeiro L, Nascimento-Costa JM and Sarmento-Ribeiro AB: Aberrant p15, p16, p53, and DAPK gene methylation in myelomagenesis: Clinical and prognostic implications. Clin Lymphoma, Myeloma Leuk. 16:713–720.e712. 2016. View Article : Google Scholar
26	Morak M, Ibisler A, Keller G, Jessen E, Laner A, Gonzales-Fassrainer D, Locher M, Massdorf T, Nissen AM, Benet-Pagès A and Holinski-Feder E: Comprehensive analysis of the MLH1 promoter region in 480 patients with colorectal cancer and 1150 controls reveals new variants including one with a heritable constitutional MLH1 epimutation. J Med Genet. 55:240–248. 2018. View Article : Google Scholar : PubMed/NCBI
27	Li J, Ye D, Wang L, Peng Y, Li Q, Deng H and Zhou C: Role of MLH1 methylation in esophageal cancer carcinogenesis and its clinical significance. Onco Targets Ther. 11:651–663. 2018. View Article : Google Scholar : PubMed/NCBI
28	Nelissen EC, van Montfoort AP, Dumoulin JC and Evers JL: Epigenetics and the placenta. Hum Reprod Update. 17:397–417. 2011. View Article : Google Scholar : PubMed/NCBI
29	Vancurova I, Gatla HR and Vancura A: HDAC/IKK inhibition therapies in solid tumors. Oncotarget. 8:34030–34031. 2017. View Article : Google Scholar : PubMed/NCBI
30	Booth L, Roberts JL, Poklepovic A, Kirkwood J and Dent P: HDAC inhibitors enhance the immunotherapy response of melanoma cells. Oncotarget. 8:83155–83170. 2017. View Article : Google Scholar : PubMed/NCBI
31	Yano M, Yasuda M, Sakaki M, Nagata K, Fujino T, Arai E, Hasebe T, Miyazawa M, Miyazawa M, Ogane N, et al: Association of histone deacetylase expression with histology and prognosis of ovarian cancer. Oncol Lett. 15:3524–3531. 2018.PubMed/NCBI
32	Gatla HR, Zou Y, Uddin MM, Singha B, Bu P, Vancura A and Vancurova I: Histone deacetylase (HDAC) inhibition induces ikappaB kinase (IKK)-dependent interleukin-8/CXCL8 expression in ovarian cancer cells. J Biol Chem. 292:5043–5054. 2017. View Article : Google Scholar : PubMed/NCBI