DNMTs inhibitor SGI‑1027 induces apoptosis in Huh7 human hepatocellular carcinoma cells

Sun,Ning; Zhang,Jialin; Zhang,Chengshuo; Zhao,Bochao; Jiao,Ao

doi:10.3892/ol.2018.9390

DNMTs inhibitor SGI‑1027 induces apoptosis in Huh7 human hepatocellular carcinoma cells

Authors:
- Ning Sun
- Jialin Zhang
- Chengshuo Zhang
- Bochao Zhao
- Ao Jiao
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Affiliations: Department of Hepatobiliary and Transplantation Surgery, The First Affiliated Hospital of China Medical University, Shenyang, Liaoning 110001, P.R. China
Published online on: September 4, 2018 https://doi.org/10.3892/ol.2018.9390
Pages: 5799-5806
Copyright: © Sun et al. This is an open access article distributed under the terms of Creative Commons Attribution License [CC BY_NC 4.0].

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Abstract

SGI‑1027, a novel class of relatively stable, highly lipophilic quinoline‑based small‑molecule inhibitors of DNA methyltransferase enzymes (DNMTs), is able to inhibit DNMTs activity, and reactivate tumor suppressor genes. However, the potential anticancer mechanisms of SGI‑1027 on human hepatocellular carcinoma (HCC) cells are still not clearly understood. Thus, the objective of the present study was to clarify the inhibitory effect of SGI‑1027 on the cell cycle and apoptosis of the Huh7 cell line. The results revealed that treatment with SGI‑1027 resulted in a significant dose‑dependent decrease in cell viability. Flow cytometric analysis identified that a 24 h treatment of SGI‑1027 resulted in cell apoptosis, and typical apoptotic nucleic alterations were observed with fluorescence microscopy following terminal deoxynucleotidyl‑transferase‑mediated dUTP nick end labeling staining. Immunoblot analysis further demonstrated that SGI‑1027 downregulated the expression of B cell lymphoma‑2 and upregulated the expression of Bcl‑associated X protein. However, no significant alterations of the cell cycle phases were observed. Overall, it is demonstrated that SGI‑1027 causes cell apoptosis via the mitochondrial‑mediated pathway, which advances current understanding of the molecular mechanisms of SGI‑1027 in HCC management.

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1	Torre LA, Bray F, Siegel RL, Ferlay J, Lortet-Tieulent J and Jemal A: Global cancer statistics, 2012. CA Cancer J Clin. 65:87–108. 2015. View Article : Google Scholar : PubMed/NCBI
2	Yeo W, Mok TS, Zee B, Leung TW, Lai PB, Lau WY, Koh J, Mo FK, Yu SC, Chan AT, et al: A randomized phase III study of doxorubicin versus cisplatin/interferon alpha-2b/doxorubicin/fluorouracil (PIAF) combination chemotherapy for unresectable hepatocellular carcinoma. J Natl Cancer Inst. 97:1532–1538. 2005. View Article : Google Scholar : PubMed/NCBI
3	Gish RG, Porta C, Lazar L, Ruff P, Feld R, Croitoru A, Feun L, Jeziorski K, Leighton J, Gallo J and Kennealey GT: Phase III randomized controlled trial comparing the survival of patients with unresectable hepatocellular carcinoma treated with nolatrexed or doxorubicin. J Clin Oncol. 25:3069–3075. 2007. View Article : Google Scholar : PubMed/NCBI
4	Wang XQ, Ongkeko WM, Chen L, Yang ZF, Lu P, Chen KK, Lopez JP, Poon RT and Fan ST: Octamer 4 (Oct4) mediates chemotherapeutic drug resistance in liver cancer cells through a potential Oct4-AKT-ATP-binding cassette G2 pathway. Hepatology. 52:528–539. 2010. View Article : Google Scholar : PubMed/NCBI
5	Chua CW and Choo SP: Targeted therapy in hepatocellular carcinoma. Int J Hepatol. 2011:3482972011. View Article : Google Scholar : PubMed/NCBI
6	Dai ZJ, Tang W, Lu WF, Gao J, Kang HF, Ma XB, Min WL, Wang XJ and Wu WY: Antiproliferative and apoptotic effects of β-elemene on human hepatoma HepG2 cells. Cancer Cell Int. 13:272013. View Article : Google Scholar : PubMed/NCBI
7	Esteller M: Epigenetic gene silencing in cancer: The DNA hypermethylome. Hum Mol Genet 16 Spec No. 1:R50–R59. 2007. View Article : Google Scholar
8	Holliday R and Pugh JE: DNA modification mechanisms and gene activity during development. Science. 187:226–232. 1975. View Article : Google Scholar : PubMed/NCBI
9	Feng S, Jacobsen SE and Reik W: Epigenetic reprogramming in plant and animal development. Science. 330:622–627. 2010. View Article : Google Scholar : PubMed/NCBI
10	Bonasio R, Tu S and Reinberg D: Molecular signals of epigenetic states. Science. 330:612–616. 2010. View Article : Google Scholar : PubMed/NCBI
11	Feinberg AP and Tycko B: The history of cancer epigenetics. Nat Rev Cancer. 4:143–153. 2004. View Article : Google Scholar : PubMed/NCBI
12	Herman JG and Baylin SB: Gene silencing in cancer in association with promoter hypermethylation. N Engl J Med. 349:2042–2054. 2003. View Article : Google Scholar : PubMed/NCBI
13	Sharma S, Kelly TK and Jones PA: Epigenetics in cancer. Carcinogenesis. 31:27–36. 2010. View Article : Google Scholar : PubMed/NCBI
14	Taby R and Issa JP: Cancer epigenetics. CA Cancer J Clin. 60:376–392. 2010. View Article : Google Scholar : PubMed/NCBI
15	Kondo Y: Epigenetic cross-talk between DNA methylation and histone modifications in human cancers. Yonsei Med J. 50:455–463. 2009. View Article : Google Scholar : PubMed/NCBI
16	Ghoshal K and Bai S: DNA methyltransferases as targets for cancer therapy. Drugs Today (Barc). 43:395–422. 2007. View Article : Google Scholar : PubMed/NCBI
17	Oki Y, Aoki E and Issa JP: Decitabine-bedside to bench. Crit Rev Oncol Hematol. 61:140–152. 2007. View Article : Google Scholar : PubMed/NCBI
18	Gorbunova V, Seluanov A, Mittelman D and Wilson JH: Genome-wide demethylation destabilizes CTG.CAG trinucleotide repeats in mammalian cells. Hum Mol Genet. 13:2979–2989. 2004. View Article : Google Scholar : PubMed/NCBI
19	Mund C, Hackanson B, Stresemann C, Lübbert M and Lyko F: Characterization of DNA demethylation effects induced by 5-Aza-2′-deoxycytidine in patients with myelodysplastic syndrome. Cancer Res. 65:7086–7090. 2005. View Article : Google Scholar : PubMed/NCBI
20	Yoo CB, Jeong S, Egger G, Liang G, Phiasivongsa P, Tang C, Redkar S and Jones PA: Delivery of 5-aza-2′-deoxycytidine to cells using oligodeoxynucleotides. Cancer Res. 67:6400–6408. 2007. View Article : Google Scholar : PubMed/NCBI
21	Datta J, Ghoshal K, Denny WA, Gamage SA, Brooke DG, Phiasivongsa P, Redkar S and Jacob ST: A new class of quinoline-based DNA hypomethylating agents reactivates tumor suppressor genes by blocking DNA methyltransferase 1 activity and inducing its degradation. Cancer Res. 69:4277–4285. 2009. View Article : Google Scholar : PubMed/NCBI
22	Gros C, Fleury L, Nahoum V, Faux C, Valente S, Labella D, Cantagrel F, Rilova E, Bouhlel MA, David-Cordonnier MH, et al: New insights on the mechanism of quinoline-based DNA Methyltransferase inhibitors. J Biol Chem. 290:6293–6302. 2015. View Article : Google Scholar : PubMed/NCBI
23	Palii SS and Robertson KD: Epigenetic control of tumor suppression. Crit Rev Eukaryot Gene Expr. 17:295–316. 2007. View Article : Google Scholar : PubMed/NCBI
24	Kulis M and Esteller M: DNA methylation and cancer. Adv Genet. 70:27–56. 2010.PubMed/NCBI
25	Garcia-Dominguez P, Dell'aversana C, Alvarez R, Altucci L and de Lera AR: Synthetic approaches to DNMT inhibitor SGI-1027 and effects on the U937 leukemia cell line. Bioorg Med Chem Lett. 23:1631–1635. 2013. View Article : Google Scholar : PubMed/NCBI
26	Ronen M, Avrahami D and Gerber D: A sensitive microfluidic platform for a high throughput DNA methylation assay. Lab Chip. 14:2354–2362. 2014. View Article : Google Scholar : PubMed/NCBI
27	Elmore S: Apoptosis: A review of programmed cell death. Toxicol Pathol. 35:495–516. 2007. View Article : Google Scholar : PubMed/NCBI
28	Renault TT, Teijido O, Antonsson B, Dejean LM and Manon S: Regulation of Bax mitochondrial localization by Bcl-2 and Bcl-x(L): Keep your friends close but your enemies closer. Int J Biochem Cell Biol. 45:64–67. 2013. View Article : Google Scholar : PubMed/NCBI
29	Hata AN, Engelman JA and Faber AC: The BCL2 family: Key mediators of the apoptotic response to targeted anticancer therapeutics. Cancer Discov. 5:475–487. 2015. View Article : Google Scholar : PubMed/NCBI
30	Siddiqui WA, Ahad A and Ahsan H: The mystery of BCL2 family: Bcl-2 proteins and apoptosis: An update. Arch Toxicol. 89:289–317. 2015. View Article : Google Scholar : PubMed/NCBI