Expression profiling of DNA methyl transferase I (DNMT1) and efficacy of a DNA-hypomethylating agent (decitabine) in combination with chemotherapy in osteosarcoma

Chaiyawat, Parunya; Sirikaew, Nutnicha; Budprom, Piyaporn; Klangjorhor, Jeerawan; Phanphaisarn, Areerak; Teeyakasem, Pimpisa; Settakorn, Jongkolnee; Pruksakorn, Dumnoensun

doi:10.1016/j.jbo.2020.100321

Cited by 7 publications

(8 citation statements)

References 25 publications

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“…So far, Decitabine has been considered more as a hypomethylating agent (32)(33)(34)(35)(36)(37) and less as a histone deacetylase inhibitor. This study investigates the histone deacetylase inhibitory status of Decitabine.…”

Section: Discussionmentioning

confidence: 99%

Investigation of Decitabine Effects on HDAC3 and HDAC7 mRNA Expression in NALM-6 and HL-60 Cancer Cell Lines

et al. 2021

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Background: Decitabine is a potent anticancer hypomethylating agent and changes the gene expression through the gene's promoter demethylation and also independently from DNA demethylation. So, the present study was designed to distinguish whether Decitabine, in addition to inhibitory effects on DNA methyltransferase, can change HDAC3 and HDAC7 mRNA expression in NALM-6 and HL-60 cancer cell lines. Methods: HL-60, NALM-6, and normal cells were cultured, and the Decitabine treatment dose was obtained (1 µM) through the MTT assay. Finally, HDAC3 and HDAC7 mRNA expression were measured by Real-Time PCR in HL-60 and NALM-6 cancerous cells before and after treatment. Furthermore, HDAC3 and HDAC7 mRNA expression in untreated HL-60 and NALM-6 cancerous cells were compared to normal cells. Results: Our results revealed that the expression of HDAC3 and HDAC7 in HL-60 and NALM-6 cells increases as compared to normal cells. After treatment of HL-60 and NALM-6 cells with Decitabine, HDAC3, and HDAC7 mRNA expression were decreased significantly. Conclusions: Our data confirmed that the effects of Decitabine are not limited to direct hypomethylation of DNMTs, but it can indirectly affect other epigenetic factors, such as HDACs activity, through converging pathways.

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Section: Discussionmentioning

confidence: 99%

Investigation of Decitabine Effects on HDAC3 and HDAC7 mRNA Expression in NALM-6 and HL-60 Cancer Cell Lines

et al. 2021

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“…The reversibility of epimutations turns them into interesting targets for the development of therapies. In osteosarcomas cell lines, the demethylating agent decitabine (5-aza-dC, a DNMT1-inhibitor) can promote the recovery of gene expression silenced by hypermethylation, resulting in reduced cell growth 29 or increased sensibility to chemotherapeutic agents at concentrations within therapeutic levels 30 . Therefore, DNA methylation profiles may directly point to robust disrupted mechanisms in osteosarcomas.…”

Section: Discussionmentioning

confidence: 99%

“…DNMT1 andDNMT3A also had extra copies in some samples. DNMT1 overexpression is a recurrent event across osteosarcomas, with a negative impact on the expression of several tumor suppressor genes 30 . DNMT3A and DNMT3B seem to have both redundant and exclusive targets; while DNMT3A remains active in adults 39 , expression of DNMT3B catalytic isoforms decreases during cell differentiation 40 .…”

Section: Discussionmentioning

confidence: 99%

DNA methylation patterns suggest the involvement of DNMT3B and TET1 in osteosarcoma development

Maschietto

Pires

Barros

et al. 2022

Preprint

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Background: Osteosarcomas commonly arise during the bone growth and remodeling in puberty, making it plausible to infer the involvement of epigenetic alterations in their development. Procedure: We investigated DNA methylation and related genetic variants in 28 primary osteosarcomas aiming to identify deregulated driver pathways. Methylation and genomic data was obtained using the Illumina HM450K beadchips and the TruSight One sequencing panel, respectively. Results: Aberrant DNA methylation was spread throughout the osteosarcomas genomes. We identified 3,146 differentially methylated CpGs comparing osteosarcomas and bone tissue samples, with high methylation heterogeneity, global hypomethylation and focal hypermethylation at CpG islands. Differentially methylated regions (DMR) were detected in 585 loci (319 hypomethylated and 266 hypermethylated), mapped to the promoter regions of 350 genes. These DMR-genes were enriched for biological processes related to skeletal system morphogenesis, proliferation, inflammatory response and signal transduction. Six tumor suppressor genes harbored deletions or promoter hypermethylation ( DLEC1, GJB2, HIC1, MIR149, PAX6, WNT5A), and four oncogenes presented gains or hypomethylation ( ASPSCR1, NOTCH4, PRDM16, RUNX3). Our analysis also revealed hypomethylation at 6p22, a region that contains several histone genes. DNMT3B gain was found to be a recurrent copy number change in osteosarcomas, providing a possible explanation for the observed phenotype of CpG island hypermethylation. Conclusions: While the detected open-sea hypomethylation likely contributes to the well-known osteosarcoma genomic instability, enriched CpG island hypermethylation suggests an underlying mechanism possibly driven by overexpression of DNMT3B likely resulting in silencing of tumor suppressors and DNA repair genes.

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“…Single‐cell studies on epigenetic modifications (Cui et al, 2017 ; Cui & Irudayaraj, 2015 ; Liu et al, 2019 ) along with sequencing have provided both broad and focused perspectives on epigenetic events and mechanisms during OS progression, which might facilitate targeted therapy. A DNA methyltransferase inhibitor, decitabine , improved the chemosensitivity of OS cells to cisplatin when used together (Chaiyawat et al, 2020 ), as well as providing an opportunity to promote OS differentiation through expression of the oestrogen receptor ER‐α (Osuna et al, 2019 ). Histone deacetylase inhibitors such as panobinostat , domatinostat, entinostat , vorinostat , trichostatin A and sodium butyrate have been tested alone (Deng et al, 2016 ; McGuire et al, 2020 ; Mu et al, 2015 ; Rao‐Bindal et al, 2013 ; Torres et al, 2020 ; Xie et al, 2016 ) or in combination with doxorubicin/cisplatin (Pettke et al, 2016 ) or decitabine (Capobianco et al, 2014 ) and have shown anti‐proliferative and anti‐metastatic effect in OS cells.…”

Section: Osteosarcomamentioning

confidence: 99%

Osteosarcoma mechanobiology and therapeutic targets

Shoaib

Fan

Irudayaraj

2021

British J Pharmacology

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Osteosarcoma is one of the most common primary tumours of the bone, with a 5-year survival rate of less than 20% after the development of metastases. Osteosarcoma is highly predisposed in Paget's disease of the bone, and both have common characteristic skeletal features due to rapid bone remodelling. Osteosarcoma prognosis is location dependent, which further emphasizes the likely contribution of the bone microenvironment in its pathogenesis. Mechanobiology describes the processes involved when mechanical cues from the changing physical microenvironment of the bone are transduced to biological pathways through mechanosensitive cellular components. Mechanobiology-driven therapies have been used to curb tumour progression by direct alteration of the physical microenvironment or inhibition of metastasis-associated mechanosensitive proteins. This review emphasizes the contribution of mechanobiology to the progression of osteosarcoma and sheds light on current mechanobiology-based therapies and potential new targets for improving disease management. Additionally, the many different 3D models currently used to study osteosarcoma mechanobiology are summarized.

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Expression profiling of DNA methyl transferase I (DNMT1) and efficacy of a DNA-hypomethylating agent (decitabine) in combination with chemotherapy in osteosarcoma

Cited by 7 publications

References 25 publications

Investigation of Decitabine Effects on HDAC3 and HDAC7 mRNA Expression in NALM-6 and HL-60 Cancer Cell Lines

Investigation of Decitabine Effects on HDAC3 and HDAC7 mRNA Expression in NALM-6 and HL-60 Cancer Cell Lines

DNA methylation patterns suggest the involvement of DNMT3B and TET1 in osteosarcoma development

Osteosarcoma mechanobiology and therapeutic targets

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