Frequent methylation of RASSF1A in synovial sarcoma and the anti-tumor effects of 5-aza-2′-deoxycytidine against synovial sarcoma cell lines

Numoto, Kunihiko; Yoshida, Aki; Sugihara, Shinsuke; Kunisada, Toshiyuki; Morimoto, Yuki; Yoneda, Yasushi; Fujita, Yuka; Nishida, Keiichiro; Ouchida, Mamoru

doi:10.1007/s00432-009-0632-2

Cited by 16 publications

(11 citation statements)

References 36 publications

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“…The silence and hypermethylation status of RASSF1A in the two HPV-negative cervical cancer cell lines (C-33A and HT-3) could be reversed by demethylating agent 5-Aza-dC treatment and the influence was concentration dependent. This is the first demonstration that the RASSf1A mRNA could be reactivated by downregulating its promoter methylation status using demethylating agent 5-Aza-dC, similar to the impact of 5-Aza-dC on RASSF1A gene in esophageal squamous cell carcinoma, synovial sarcoma and melanoma (36)(37)(38). Our results showed that the methylation status and expression of RASSF1A gene between the two HPV-negative cervical cancer cell lines (C-33A and HT-3) and three HPV-positive cervical cancer cell lines (HeLa, SiHa and CaSki) were significantly different.…”

Section: Discussionmentioning

confidence: 54%

HPV16 oncogenes E6 or/and E7 may influence the methylation status of RASSFIA gene promoter region in cervical cancer cell line HT-3

Yin

Wang

Wang³

et al. 2017

Oncology Reports

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Both human papillomavirus (HPV) infection and the aberrant Ras associated domain family gene 1A (RASSF1A) promoter methylation status participate in the pathogenesis of cervical cancer. Some studies suggest that E6, and E7 are involved in the pathogenetic mechanisms of RASSF1A. We mainly explored a possible involvement of HPV16 oncogenes E6 or/and E7 in RASSF1A promoter methylation status and possible roles of RASSF1A gene methylation in cervical cancer. Bisulfite genomic sequencing (BGS) PCR combined with TA clone, methylation-specific PCR (MSP) were used to analyze methylation status of the RASSF1A gene promoter in HPV16/18-positive and HPV-negative cervical cancer cell lines; ectopically expressed HPV16 E6, E7 and E6/E7 cervical cancer cell lines; normal cervical and cervical cancer tissues. The mRNA and protein expression of RASSF1A was detected by RT-PCR and western blotting. Re-expression and downregulated promoter methylation status were detected in the ectopically expressed HPV16 E6 and E7 cervical cancer cell line HT-3. The methylation status and expression of RASSF1A could be downregulated or reactivated by 5-Aza-dc in HT-3 and C33A cells. Additionally, statistics showed significant hypermethylation of RASSF1A in cervical cancer samples compared to that in normal cervical samples (P<0.05). The false negative rate (FNR) was 6.25% by HC2 method, when reconfirmed by HPV detection combining the MY09/11, GP5+/6+ and SPF1/2 methods. The ectopic expression of HPV16 E6 and/or E7 may be involved in aberrant methylation and expression of the RASSF1A gene. RASSF1A gene expression could be regulated by its promoter methylation status. Additionally, the false negativity of the HPV detection may contribute to the uncertain relationship between HPV infection and aberrant RASSF1A promoter methylation.

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Section: Discussionmentioning

confidence: 54%

HPV16 oncogenes E6 or/and E7 may influence the methylation status of RASSFIA gene promoter region in cervical cancer cell line HT-3

Yin

Wang

Wang³

et al. 2017

Oncology Reports

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“…Decitabine (5-aza-2'-deoxycytidin; DAC) is an epigenetic therapeutic agent that inhibits DNA methylation, which has been approved for the treatment of myelodysplastic syndrome and older patients with acute myeloid leukemia (AML) (11,12). In addition to its use in hematological malignancy, DAC also exhibits antineoplastic effects against solid tumors (13)(14)(15)(16). The molecular mechanism underlying its antitumor activity is that DAC induces DNMT inhibition, which contributes to DNA hypomethylation, gene activation, cell differentiation and apoptosis (17,18).…”

Section: Introductionmentioning

confidence: 99%

Decitabine enhances bortezomib treatment in RPMI 8226 multiple myeloma cells

Cao

Qiu

et al. 2016

Molecular Medicine Reports

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The present study investigated the interactions between decitabine (DAC) and bortezomib (BTZ) in RPMI 8226 multiple myeloma (MM) cells. Cells were exposed to DAC alone and in combination with BTZ for 48 h. A Cell Counting Kit‑8 assay was performed to assess the rate of proliferation inhibition in the cells. Cell apoptosis was investigated by Annexin V-fluorescein isothiocyanate and propidium iodide staining. Flow cytometry was used to detect the different cell cycle stages. Western blotting was performed to analyze the protein expression levels of poly(ADP‑ribose) polymerase 1 (PARP‑1), caspase‑3, ‑9 and DNA (cytosine‑5‑)‑methyltransferase 1 (DNMT1). Reverse transcription‑quantitative polymerase chain reaction was used to assess DNMT1 gene expression. The combination of DAC and BTZ increased the proliferation inhibition, apoptotic rate and G0‑G1 arrest compared with use of a single therapeutic agent. In addition, the combination treatment enhanced PARP‑1 cleavage, caspase‑3 and caspase‑9 activation and downregulated the protein and mRNA expression levels of DNMT1. Therefore, the current study determined that the combination of BTZ and the epigenetic agent DAC may be a novel therapeutic strategy to improve the efficacy of BTZ in patients with MM.

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“…While in all reported cases the addition of a DNA-MI was able to reverse expression of the initially DNA-methylation suppressed gene, the effect of that reversal was either not examined when studied in rhabdomyosarcomas (16), found to result in minor apoptosis when studied in osteosarcomas (17), or extremely dependent on time of exposure and choice of cell line (18) even within the same sarcoma subtype. In contrast, pre-clinical data indicates that treatment of multiple sarcoma subtypes with multiple HDACIs demonstrates significant cellular growth inhibition at (depending on HDACI) doses therapeutically active in hematologic malignancies (19–24).…”

Section: Introductionmentioning

confidence: 99%

Chromatin Structure Predicts Epigenetic Therapy Responsiveness in Sarcoma

Mills

Hricik

Siddiqi

et al. 2011

Molecular Cancer Therapeutics

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To formally explore the potential therapeutic effect of histone deacetylase inhibitors (HDACI) and DNA-methyltransferase inhibitors (DNA-MI) on sarcomas, we treated a large sarcoma cell line panel with five different HDACIs in the absence and presence of the DNA-MI decitabine. We observed that the IC 50 value of each HDACI was consistent for all cell lines whereas decitabine as a single agent showed no growth inhibition at standard doses. Combination HDACI/DNA-MI therapy showed a preferential synergism for specific sarcoma cell lines. Subsequently, we identified and validated (in vitro and in vivo) a two-gene set signature (high CUGBP2; low RHOJ) that associated with the synergistic phenotype. We further uncover that the epigenetic synergism leading to specific upregulation of CDKI p21 in specific cell lines is a function of the differences in the degree of baseline chromatin modification. Finally, we show that these chromatin and gene expression patterns are similarly present in the majority of high-grade primary sarcomas. Our results provide the first demonstration of a gene set that can predict responsiveness to HDACI/DNA-MI and links this responsiveness mechanistically to the baseline chromatin structure. Mol Cancer Ther; 10(2); 313-24. Ó2011 AACR.

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Frequent methylation of RASSF1A in synovial sarcoma and the anti-tumor effects of 5-aza-2′-deoxycytidine against synovial sarcoma cell lines

Abstract: This is the first report showing the anti-tumor effect of 5-Aza-dC on synovial sarcoma. 5-Aza-dC is suggested to have a good therapeutic potential against synovial sarcoma.

Cited by 16 publications

References 36 publications

HPV16 oncogenes E6 or/and E7 may influence the methylation status of RASSFIA gene promoter region in cervical cancer cell line HT-3

HPV16 oncogenes E6 or/and E7 may influence the methylation status of RASSFIA gene promoter region in cervical cancer cell line HT-3

Decitabine enhances bortezomib treatment in RPMI 8226 multiple myeloma cells

Chromatin Structure Predicts Epigenetic Therapy Responsiveness in Sarcoma

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