Differential Induction of Apoptosis and Senescence by the DNA Methyltransferase Inhibitors 5-Azacytidine and 5-Aza-2′-Deoxycytidine in Solid Tumor Cells

Venturelli, Sascha; Berger, Alexander; Weiland, Timo; Eßmann, Frank; Waibel, Michaela; Nuebling, Tina; Häcker, Sabine; Schenk, Martin; Schulze‐Osthoff, Klaus; Salih, Helmut R.; Fulda, Simone; Sipos, Bence; Johnstone, Ricky W.; Lauer, Ulrich M.; Bitzer, Michael

doi:10.1158/1535-7163.mct-13-0137

Cited by 85 publications

(67 citation statements)

References 45 publications

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“…As reported previously in other settings, 21,51 the two DNMT inhibitors AZA and DAC induced different responses in esophageal cancer cells. Hence, only AZA was further tested in combinations with HDACi in esophageal cancer cells.…”

Section: Discussionsupporting

confidence: 65%

“…[17][18][19] In other solid gastrointestinal tract cancers, HDACi or AZA showed anti-tumor activity in model systems, but its clinical relevance is still under investigation. 20,21 Since solid tumors frequently exhibit major intra-and inter-tumoral heterogeneity, it is not surprising that HDACi and AZA treatment was so far only approved for hematological diseases. [22][23][24] The mechanism of action of HDACi or DNMT inhibitors is mainly via their effect on altering, respective re-activating transcription of silenced tumor suppressor genes.…”

Section: Introductionmentioning

confidence: 99%

“…26,27 Moreover, HDACi show major cell typespecific, respective potentially cancer cell-selective effects 28,29 and include distinct patterns of induction of apoptosis, differentiation, cell cycle arrest, or even immunomodulation (for HDACi). 16,21,30,31 The distinct cellular effects may be triggered by cell type-specific patterns of transcriptional re-expression, as well as oxidative stress or DNA repair. 32,33 Importantly, synergistic effects of HDACi and the DNMT inhibitor DAC were reported for growth inhibition, DNA damage, and apoptosis induction in different tumor entities.…”

Section: Introductionmentioning

confidence: 99%

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Selective inhibition of esophageal cancer cells by combination of HDAC inhibitors and Azacytidine

Ahrens¹,

Timme

Hoeppner³

et al. 2015

Epigenetics

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Esophageal cancers are highly aggressive tumors with poor prognosis despite some recent advances in surgical and radiochemotherapy treatment options. This study addressed the feasibility of drugs targeting epigenetic modifiers in esophageal squamous cell carcinoma (ESCC) and esophageal adenocarcinoma (EAC) cells. We tested inhibition of histone deacetylases (HDACs) by SAHA, MS-275, and FK228, inhibition of DNA methyltransferases by Azacytidine (AZA) and Decitabine (DAC), and the effect of combination treatment using both types of drugs. The drug targets, HDAC1/2/3 and DNMT1, were expressed in normal esophageal epithelium and tumor cells of ESCC or EAC tissue specimens, as well as in non-neoplastic esophageal epithelial (Het-1A), ESCC (OE21, Kyse-270, Kyse-410), and EAC (OE33, SK-GT-4) cell lines. In vitro, HDAC activity, histone acetylation, and p21 expression were similarly affected in non-neoplastic, ESCC, and EAC cell lines post inhibitor treatment. Combined MS-275/AZA treatment, however, selectively targeted esophageal cancer cell lines by inducing DNA damage, cell viability loss, and apoptosis, and by decreasing cell migration. Non-neoplastic Het-1A cells were protected against HDACi (MS-275)/AZA treatment. RNA transcriptome analyses post MS-275 and/or AZA treatment identified novel regulated candidate genes (up: BCL6, Hes2; down: FAIM, MLKL), which were specifically associated with the treatment responses of esophageal cancer cells. In summary, combined HDACi/AZA treatment is efficient and selective for the targeting of esophageal cancer cells, despite similar target expression of normal and esophageal cancer epithelium, in vitro and in human esophageal carcinomas. The precise mechanisms of action of treatment responses involve novel candidate genes regulated by HDACi/AZA in esophageal cancer cells. Together, targeting of epigenetic modifiers in esophageal cancers may represent a potential future therapeutic approach.

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Section: Discussionsupporting

confidence: 65%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Selective inhibition of esophageal cancer cells by combination of HDAC inhibitors and Azacytidine

Ahrens¹,

Timme

Hoeppner³

et al. 2015

Epigenetics

View full text Add to dashboard Cite

show abstract

“…According to this result, Bitzer et al reported that inhibition of DNMT-1 through 5-azacytidine in human hepatoma, colon, renal, and lung cancer cells caused apoptosis. 42 The demethylation and reexpression of TSGs such as BNIP3 and SPARC after reducing DNMT-1 expression may be responsible for decreased cell proliferation in pancreatic cancer cells.…”

Section: Discussionmentioning

confidence: 99%

MicroRNA-148b and microRNA-152 reactivate tumor suppressor genes through suppression of DNA methyltransferase-1 gene in pancreatic cancer cell lines

Azizi

Teimoori‐Toolabi

Arzanani

et al. 2014

Cancer Biology & Therapy

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Overexpression of DNA methyltransferase 1 (DNMT-1) is observed mostly in pancreatic cancer and it can cause tumor suppressor genes silencing in this disease. Recent studies suggest that abnormal expressions of microRNAs (miRs) are involved in pathogenesis of different types of human cancers including pancreatic cancer. In this study we aimed to investigate the effect of miR-148b and -152 on reverting the tumorigenic phenotype of pancreatic cancer cell lines. In order to investigate whether miR-148b and -152 are involved in the regulation of DNMT-1, luciferase reporter assay was used and confirmed that the DNMT-1 mRNA could be a target for miR-148b and miR-152. Furthermore, overexpression of miR-148b and -152 in pancreatic cancer cell lines (MIA PaCa-2 and AsPC-1) decreased DNMT-1 expression (53% and 59% respectively), returned DNA methylation to normal patterns and induced re-expression of tumor suppressor genes, like BNIP3 (4.7- and 3.8-fold) and SPARC (5.3- and 2.9-fold) for miR-148b and -152 respectively. Moreover, the introduced miR-148b and -152 could inhibit the proliferation of MIA PaCa-2 (35% and 37% respectively) and AsPC-1 (39% and 40% respectively) cell lines. The apoptosis rates of MIA PaCa-1 after treatment with miR-148b and -152 were 10% and 8% respectively; while these rates in AsPC-1 were 16% and 11% respectively. Conclusively these findings mean that miRs that are targeting DNMT-1 and modifying methylation status of tumor suppressor genes such as BNIP3 and SPARC can be applied in killing the pancreatic cancer cells and decreasing the tumorigenicity of these cells.

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“…Several genes, including TFPI2, CDH1 and ACP1, have demonstrated aberrant methylation in the serum or tissue of HCC patients and thus hold clinical potential for HCC diagnosis and prognosis (Sun et al 2013;Dou et al 2016;Qiu et al 2016). Furthermore, demethylating agents might reverse abnormal methylation (Perret 2011) and might thus represent a potential epigenetic cancer treatment strategy (Venturelli et al 2013). Therefore, further study of abnormal methylation could provide a new avenue for diagnosing and treating HCC.…”

Section: Introductionmentioning

confidence: 99%

Hypomethylated Ubiquitin-Conjugating Enzyme2 Q1 (UBE2Q1) Gene Promoter in the Serum Is a Promising Biomarker for Hepatitis B Virus-Associated Hepatocellular Carcinoma

Fan

et al. 2017

Tohoku J. Exp. Med.

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Aberrant DNA methylation, which can be detected in circulating cell-free DNA (cfDNA), is one of the major epigenetic alterations in hepatocellular carcinoma (HCC). UBE2Q1, a putative member of the ubiquitinconjugating enzyme family, might play substantial roles in tumorigenesis. However, the methylation status of the UBE2Q1 gene in HCC remains unknown. We aimed to determine the methylation status of the UBE2Q1 gene promoter and to evaluate its potential clinical significance for HCC detection. The methylation-specific polymerase chain reaction (MSP) assay was used to detect the UBE2Q1 gene methylation status in serum samples from 80 patients with hepatitis B virus (HBV)-related HCC, 40 patients with liver cirrhosis (LC), 40 patients with chronic hepatitis B (CHB), and 20 healthy controls (HCs). Significantly lower methylation frequencies were detected in HCC patients (33.75%) compared with LC patients (55.00%, p = 0.026) and CHB patients (60.00%, p = 0.006) and HCs (65.00%, p = 0.011). Hypomethylation of the UBE2Q1 gene was negatively associated with the tumor node metastasis stage (r s = −0.30, p = 0.008). The UBE2Q1 gene methylation status combined with alpha fetoprotein using cut-off points of 20, 200 and 400 ng/ml showed sensitivity and specificity values of 58.8% and 75.0%, 53.8% and 87.5%, and 37.5% and 88.7%, respectively, and yielded a significantly increased area under the ROC curve (0.720, 0.760 and 0.694, respectively) for discriminating HCC from LC and CHB. Our study results suggest that hypomethylation of the UBE2Q1 gene promoter is a potential biomarker for detecting HBV-associated HCC.

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Differential Induction of Apoptosis and Senescence by the DNA Methyltransferase Inhibitors 5-Azacytidine and 5-Aza-2′-Deoxycytidine in Solid Tumor Cells

Cited by 85 publications

References 45 publications

Selective inhibition of esophageal cancer cells by combination of HDAC inhibitors and Azacytidine

Selective inhibition of esophageal cancer cells by combination of HDAC inhibitors and Azacytidine

MicroRNA-148b and microRNA-152 reactivate tumor suppressor genes through suppression of DNA methyltransferase-1 gene in pancreatic cancer cell lines

Hypomethylated Ubiquitin-Conjugating Enzyme2 Q1 (UBE2Q1) Gene Promoter in the Serum Is a Promising Biomarker for Hepatitis B Virus-Associated Hepatocellular Carcinoma

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