Decitabine-induced DNA methylation-mediated transcriptomic reprogramming in human breast cancer cell lines; the impact of DCK overexpression
Decitabine (DAC), a DNA methyltransferase (DNMT) inhibitor, is tested in combination with conventional anticancer drugs as a treatment option for various solid tumors. Although epigenome modulation provides a promising avenue in treating resistant cancer types, more studies are required to evaluate...
| Main Authors: | , , , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Frontiers Media S.A.
2022-10-01
|
| Series: | Frontiers in Pharmacology |
| Subjects: | |
| Online Access: | https://www.frontiersin.org/articles/10.3389/fphar.2022.991751/full |
| _version_ | 1811242559470567424 |
|---|---|
| author | Verona Buocikova Silvia Tyciakova Eleftherios Pilalis Chara Mastrokalou Maria Urbanova Miroslava Matuskova Lucia Demkova Veronika Medova Eleonora Marta Longhin Elise Rundén-Pran Maria Dusinska Ivan Rios-Mondragon Mihaela Roxana Cimpan Alena Gabelova Andrea Soltysova Andrea Soltysova Bozena Smolkova Aristotelis Chatziioannou Aristotelis Chatziioannou |
| author_facet | Verona Buocikova Silvia Tyciakova Eleftherios Pilalis Chara Mastrokalou Maria Urbanova Miroslava Matuskova Lucia Demkova Veronika Medova Eleonora Marta Longhin Elise Rundén-Pran Maria Dusinska Ivan Rios-Mondragon Mihaela Roxana Cimpan Alena Gabelova Andrea Soltysova Andrea Soltysova Bozena Smolkova Aristotelis Chatziioannou Aristotelis Chatziioannou |
| author_sort | Verona Buocikova |
| collection | DOAJ |
| description | Decitabine (DAC), a DNA methyltransferase (DNMT) inhibitor, is tested in combination with conventional anticancer drugs as a treatment option for various solid tumors. Although epigenome modulation provides a promising avenue in treating resistant cancer types, more studies are required to evaluate its safety and ability to normalize the aberrant transcriptional profiles. As deoxycytidine kinase (DCK)-mediated phosphorylation is a rate-limiting step in DAC metabolic activation, we hypothesized that its intracellular overexpression could potentiate DAC’s effect on cell methylome and thus increase its therapeutic efficacy. Therefore, two breast cancer cell lines, JIMT-1 and T-47D, differing in their molecular characteristics, were transfected with a DCK expression vector and exposed to low-dose DAC (approximately IC20). Although transfection resulted in a significant DCK expression increase, further enhanced by DAC exposure, no transfection-induced changes were found at the global DNA methylation level or in cell viability. In parallel, an integrative approach was applied to decipher DAC-induced, methylation-mediated, transcriptomic reprogramming. Besides large-scale hypomethylation, accompanied by up-regulation of gene expression across the entire genome, DAC also induced hypermethylation and down-regulation of numerous genes in both cell lines. Interestingly, TET1 and TET2 expression halved in JIMT-1 cells after DAC exposure, while DNMTs’ changes were not significant. The protein digestion and absorption pathway, containing numerous collagen and solute carrier genes, ranking second among membrane transport proteins, was the top enriched pathway in both cell lines when hypomethylated and up-regulated genes were considered. Moreover, the calcium signaling pathway, playing a significant role in drug resistance, was among the top enriched in JIMT-1 cells. Although low-dose DAC demonstrated its ability to normalize the expression of tumor suppressors, several oncogenes were also up-regulated, a finding, that supports previously raised concerns regarding its broad reprogramming potential. Importantly, our research provides evidence about the involvement of active demethylation in DAC-mediated transcriptional reprogramming. |
| first_indexed | 2024-04-12T13:54:06Z |
| format | Article |
| id | doaj.art-5bc2b77aace34b56b39120aa94a4b5ef |
| institution | Directory Open Access Journal |
| issn | 1663-9812 |
| language | English |
| last_indexed | 2024-04-12T13:54:06Z |
| publishDate | 2022-10-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Pharmacology |
| spelling | doaj.art-5bc2b77aace34b56b39120aa94a4b5ef2022-12-22T03:30:26ZengFrontiers Media S.A.Frontiers in Pharmacology1663-98122022-10-011310.3389/fphar.2022.991751991751Decitabine-induced DNA methylation-mediated transcriptomic reprogramming in human breast cancer cell lines; the impact of DCK overexpressionVerona Buocikova0Silvia Tyciakova1Eleftherios Pilalis2Chara Mastrokalou3Maria Urbanova4Miroslava Matuskova5Lucia Demkova6Veronika Medova7Eleonora Marta Longhin8Elise Rundén-Pran9Maria Dusinska10Ivan Rios-Mondragon11Mihaela Roxana Cimpan12Alena Gabelova13Andrea Soltysova14Andrea Soltysova15Bozena Smolkova16Aristotelis Chatziioannou17Aristotelis Chatziioannou18Cancer Research Institute, Biomedical Research Center of the Slovak Academy of Sciences, Bratislava, SlovakiaCancer Research Institute, Biomedical Research Center of the Slovak Academy of Sciences, Bratislava, Slovakiae-NIOS Applications P.C., Athens, Greecee-NIOS Applications P.C., Athens, GreeceCancer Research Institute, Biomedical Research Center of the Slovak Academy of Sciences, Bratislava, SlovakiaCancer Research Institute, Biomedical Research Center of the Slovak Academy of Sciences, Bratislava, SlovakiaCancer Research Institute, Biomedical Research Center of the Slovak Academy of Sciences, Bratislava, SlovakiaInstitute of Clinical and Translational Research, Biomedical Research Center, Slovak Academy of Sciences, Bratislava, SlovakiaHealth Effects Laboratory, NILU-Norwegian Institute for Air Research, Kjeller, NorwayHealth Effects Laboratory, NILU-Norwegian Institute for Air Research, Kjeller, NorwayHealth Effects Laboratory, NILU-Norwegian Institute for Air Research, Kjeller, NorwayDepartment of Clinical Dentistry, University of Bergen, Bergen, NorwayDepartment of Clinical Dentistry, University of Bergen, Bergen, NorwayCancer Research Institute, Biomedical Research Center of the Slovak Academy of Sciences, Bratislava, SlovakiaInstitute of Clinical and Translational Research, Biomedical Research Center, Slovak Academy of Sciences, Bratislava, SlovakiaDepartment of Molecular Biology, Faculty of Natural Sciences, Comenius University in Bratislava, Bratislava, SlovakiaCancer Research Institute, Biomedical Research Center of the Slovak Academy of Sciences, Bratislava, Slovakiae-NIOS Applications P.C., Athens, GreeceCenter of Systems Biology, Biomedical Research Foundation of the Academy of Athens, Athens, GreeceDecitabine (DAC), a DNA methyltransferase (DNMT) inhibitor, is tested in combination with conventional anticancer drugs as a treatment option for various solid tumors. Although epigenome modulation provides a promising avenue in treating resistant cancer types, more studies are required to evaluate its safety and ability to normalize the aberrant transcriptional profiles. As deoxycytidine kinase (DCK)-mediated phosphorylation is a rate-limiting step in DAC metabolic activation, we hypothesized that its intracellular overexpression could potentiate DAC’s effect on cell methylome and thus increase its therapeutic efficacy. Therefore, two breast cancer cell lines, JIMT-1 and T-47D, differing in their molecular characteristics, were transfected with a DCK expression vector and exposed to low-dose DAC (approximately IC20). Although transfection resulted in a significant DCK expression increase, further enhanced by DAC exposure, no transfection-induced changes were found at the global DNA methylation level or in cell viability. In parallel, an integrative approach was applied to decipher DAC-induced, methylation-mediated, transcriptomic reprogramming. Besides large-scale hypomethylation, accompanied by up-regulation of gene expression across the entire genome, DAC also induced hypermethylation and down-regulation of numerous genes in both cell lines. Interestingly, TET1 and TET2 expression halved in JIMT-1 cells after DAC exposure, while DNMTs’ changes were not significant. The protein digestion and absorption pathway, containing numerous collagen and solute carrier genes, ranking second among membrane transport proteins, was the top enriched pathway in both cell lines when hypomethylated and up-regulated genes were considered. Moreover, the calcium signaling pathway, playing a significant role in drug resistance, was among the top enriched in JIMT-1 cells. Although low-dose DAC demonstrated its ability to normalize the expression of tumor suppressors, several oncogenes were also up-regulated, a finding, that supports previously raised concerns regarding its broad reprogramming potential. Importantly, our research provides evidence about the involvement of active demethylation in DAC-mediated transcriptional reprogramming.https://www.frontiersin.org/articles/10.3389/fphar.2022.991751/fulldecitabineDNA methylationgene expressiondeoxycytidine kinasecytosine deaminasewhole-genome analysis |
| spellingShingle | Verona Buocikova Silvia Tyciakova Eleftherios Pilalis Chara Mastrokalou Maria Urbanova Miroslava Matuskova Lucia Demkova Veronika Medova Eleonora Marta Longhin Elise Rundén-Pran Maria Dusinska Ivan Rios-Mondragon Mihaela Roxana Cimpan Alena Gabelova Andrea Soltysova Andrea Soltysova Bozena Smolkova Aristotelis Chatziioannou Aristotelis Chatziioannou Decitabine-induced DNA methylation-mediated transcriptomic reprogramming in human breast cancer cell lines; the impact of DCK overexpression Frontiers in Pharmacology decitabine DNA methylation gene expression deoxycytidine kinase cytosine deaminase whole-genome analysis |
| title | Decitabine-induced DNA methylation-mediated transcriptomic reprogramming in human breast cancer cell lines; the impact of DCK overexpression |
| title_full | Decitabine-induced DNA methylation-mediated transcriptomic reprogramming in human breast cancer cell lines; the impact of DCK overexpression |
| title_fullStr | Decitabine-induced DNA methylation-mediated transcriptomic reprogramming in human breast cancer cell lines; the impact of DCK overexpression |
| title_full_unstemmed | Decitabine-induced DNA methylation-mediated transcriptomic reprogramming in human breast cancer cell lines; the impact of DCK overexpression |
| title_short | Decitabine-induced DNA methylation-mediated transcriptomic reprogramming in human breast cancer cell lines; the impact of DCK overexpression |
| title_sort | decitabine induced dna methylation mediated transcriptomic reprogramming in human breast cancer cell lines the impact of dck overexpression |
| topic | decitabine DNA methylation gene expression deoxycytidine kinase cytosine deaminase whole-genome analysis |
| url | https://www.frontiersin.org/articles/10.3389/fphar.2022.991751/full |
| work_keys_str_mv | AT veronabuocikova decitabineinduceddnamethylationmediatedtranscriptomicreprogramminginhumanbreastcancercelllinestheimpactofdckoverexpression AT silviatyciakova decitabineinduceddnamethylationmediatedtranscriptomicreprogramminginhumanbreastcancercelllinestheimpactofdckoverexpression AT eleftheriospilalis decitabineinduceddnamethylationmediatedtranscriptomicreprogramminginhumanbreastcancercelllinestheimpactofdckoverexpression AT charamastrokalou decitabineinduceddnamethylationmediatedtranscriptomicreprogramminginhumanbreastcancercelllinestheimpactofdckoverexpression AT mariaurbanova decitabineinduceddnamethylationmediatedtranscriptomicreprogramminginhumanbreastcancercelllinestheimpactofdckoverexpression AT miroslavamatuskova decitabineinduceddnamethylationmediatedtranscriptomicreprogramminginhumanbreastcancercelllinestheimpactofdckoverexpression AT luciademkova decitabineinduceddnamethylationmediatedtranscriptomicreprogramminginhumanbreastcancercelllinestheimpactofdckoverexpression AT veronikamedova decitabineinduceddnamethylationmediatedtranscriptomicreprogramminginhumanbreastcancercelllinestheimpactofdckoverexpression AT eleonoramartalonghin decitabineinduceddnamethylationmediatedtranscriptomicreprogramminginhumanbreastcancercelllinestheimpactofdckoverexpression AT eliserundenpran decitabineinduceddnamethylationmediatedtranscriptomicreprogramminginhumanbreastcancercelllinestheimpactofdckoverexpression AT mariadusinska decitabineinduceddnamethylationmediatedtranscriptomicreprogramminginhumanbreastcancercelllinestheimpactofdckoverexpression AT ivanriosmondragon decitabineinduceddnamethylationmediatedtranscriptomicreprogramminginhumanbreastcancercelllinestheimpactofdckoverexpression AT mihaelaroxanacimpan decitabineinduceddnamethylationmediatedtranscriptomicreprogramminginhumanbreastcancercelllinestheimpactofdckoverexpression AT alenagabelova decitabineinduceddnamethylationmediatedtranscriptomicreprogramminginhumanbreastcancercelllinestheimpactofdckoverexpression AT andreasoltysova decitabineinduceddnamethylationmediatedtranscriptomicreprogramminginhumanbreastcancercelllinestheimpactofdckoverexpression AT andreasoltysova decitabineinduceddnamethylationmediatedtranscriptomicreprogramminginhumanbreastcancercelllinestheimpactofdckoverexpression AT bozenasmolkova decitabineinduceddnamethylationmediatedtranscriptomicreprogramminginhumanbreastcancercelllinestheimpactofdckoverexpression AT aristotelischatziioannou decitabineinduceddnamethylationmediatedtranscriptomicreprogramminginhumanbreastcancercelllinestheimpactofdckoverexpression AT aristotelischatziioannou decitabineinduceddnamethylationmediatedtranscriptomicreprogramminginhumanbreastcancercelllinestheimpactofdckoverexpression |