Revealing role of epigenetic modifiers and DNA oxidation in cell-autonomous regulation of Cancer stem cells
Abstract Background Breast cancer cells (BCCs) can remain undetected for decades in dormancy. These quiescent cells are similar to cancer stem cells (CSCs); hence their ability to initiate tertiary metastasis. Dormancy can be regulated by components of the tissue microenvironment such as bone marrow...
| Main Authors: | , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
BMC
2024-02-01
|
| Series: | Cell Communication and Signaling |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s12964-024-01512-1 |
| _version_ | 1797273795935862784 |
|---|---|
| author | Alejandra I. Ferrer-Diaz Garima Sinha Andrew Petryna Ruth Gonzalez-Bermejo Yannick Kenfack Oluwadamilola Adetayo Shyam A. Patel Anupama Hooda-Nehra Pranela Rameshwar |
| author_facet | Alejandra I. Ferrer-Diaz Garima Sinha Andrew Petryna Ruth Gonzalez-Bermejo Yannick Kenfack Oluwadamilola Adetayo Shyam A. Patel Anupama Hooda-Nehra Pranela Rameshwar |
| author_sort | Alejandra I. Ferrer-Diaz |
| collection | DOAJ |
| description | Abstract Background Breast cancer cells (BCCs) can remain undetected for decades in dormancy. These quiescent cells are similar to cancer stem cells (CSCs); hence their ability to initiate tertiary metastasis. Dormancy can be regulated by components of the tissue microenvironment such as bone marrow mesenchymal stem cells (MSCs) that release exosomes to dedifferentiate BCCs into CSCs. The exosomes cargo includes histone 3, lysine 4 (H3K4) methyltransferases - KMT2B and KMT2D. A less studied mechanism of CSC maintenance is the process of cell-autonomous regulation, leading us to examine the roles for KMT2B and KMT2D in sustaining CSCs, and their potential as drug targets. Methods Use of pharmacological inhibitor of H3K4 (WDR5–0103), knockdown (KD) of KMT2B or KMT2D in BCCs, real time PCR, western blot, response to chemotherapy, RNA-seq, and flow cytometry for circulating markers of CSCs and DNA hydroxylases in BC patients. In vivo studies using a dormancy model studied the effects of KMT2B/D to chemotherapy. Results H3K4 methyltransferases sustain cell autonomous regulation of CSCs, impart chemoresistance, maintain cycling quiescence, and reduce migration and proliferation of BCCs. In vivo studies validated KMT2’s role in dormancy and identified these genes as potential drug targets. DNA methylase (DNMT), predicted within a network with KMT2 to regulate CSCs, was determined to sustain circulating CSC-like in the blood of patients. Conclusion H3K4 methyltransferases and DNA methylation mediate cell autonomous regulation to sustain CSC. The findings provide crucial insights into epigenetic regulatory mechanisms underlying BC dormancy with KMT2B and KMT2D as potential therapeutic targets, along with standard care. Stem cell and epigenetic markers in circulating BCCs could monitor treatment response and this could be significant for long BC remission to partly address health disparity. |
| first_indexed | 2024-03-07T14:49:20Z |
| format | Article |
| id | doaj.art-1f56bd6110494069ba55e62935daf8ed |
| institution | Directory Open Access Journal |
| issn | 1478-811X |
| language | English |
| last_indexed | 2024-03-07T14:49:20Z |
| publishDate | 2024-02-01 |
| publisher | BMC |
| record_format | Article |
| series | Cell Communication and Signaling |
| spelling | doaj.art-1f56bd6110494069ba55e62935daf8ed2024-03-05T19:46:46ZengBMCCell Communication and Signaling1478-811X2024-02-0122112210.1186/s12964-024-01512-1Revealing role of epigenetic modifiers and DNA oxidation in cell-autonomous regulation of Cancer stem cellsAlejandra I. Ferrer-Diaz0Garima Sinha1Andrew Petryna2Ruth Gonzalez-Bermejo3Yannick Kenfack4Oluwadamilola Adetayo5Shyam A. Patel6Anupama Hooda-Nehra7Pranela Rameshwar8Department of Medicine – Division of Hematology/Oncology, Rutgers, New Jersey Medical SchoolDepartment of Medicine – Division of Hematology/Oncology, Rutgers, New Jersey Medical SchoolDepartment of Medicine – Division of Hematology/Oncology, Rutgers, New Jersey Medical SchoolUniversity of Puerto RicoDepartment of Medicine – Division of Hematology/Oncology, Rutgers, New Jersey Medical SchoolRutgers School of Dental MedicineDivision of Hematology and Oncology, Department of Medicine, UMass Memorial Medical Center, UMass Chan Medical SchoolDepartment of Medicine – Division of Hematology/Oncology, Rutgers, New Jersey Medical SchoolDepartment of Medicine – Division of Hematology/Oncology, Rutgers, New Jersey Medical SchoolAbstract Background Breast cancer cells (BCCs) can remain undetected for decades in dormancy. These quiescent cells are similar to cancer stem cells (CSCs); hence their ability to initiate tertiary metastasis. Dormancy can be regulated by components of the tissue microenvironment such as bone marrow mesenchymal stem cells (MSCs) that release exosomes to dedifferentiate BCCs into CSCs. The exosomes cargo includes histone 3, lysine 4 (H3K4) methyltransferases - KMT2B and KMT2D. A less studied mechanism of CSC maintenance is the process of cell-autonomous regulation, leading us to examine the roles for KMT2B and KMT2D in sustaining CSCs, and their potential as drug targets. Methods Use of pharmacological inhibitor of H3K4 (WDR5–0103), knockdown (KD) of KMT2B or KMT2D in BCCs, real time PCR, western blot, response to chemotherapy, RNA-seq, and flow cytometry for circulating markers of CSCs and DNA hydroxylases in BC patients. In vivo studies using a dormancy model studied the effects of KMT2B/D to chemotherapy. Results H3K4 methyltransferases sustain cell autonomous regulation of CSCs, impart chemoresistance, maintain cycling quiescence, and reduce migration and proliferation of BCCs. In vivo studies validated KMT2’s role in dormancy and identified these genes as potential drug targets. DNA methylase (DNMT), predicted within a network with KMT2 to regulate CSCs, was determined to sustain circulating CSC-like in the blood of patients. Conclusion H3K4 methyltransferases and DNA methylation mediate cell autonomous regulation to sustain CSC. The findings provide crucial insights into epigenetic regulatory mechanisms underlying BC dormancy with KMT2B and KMT2D as potential therapeutic targets, along with standard care. Stem cell and epigenetic markers in circulating BCCs could monitor treatment response and this could be significant for long BC remission to partly address health disparity.https://doi.org/10.1186/s12964-024-01512-1Breast cancerDormancyEpigenomeResistanceBreast cancerCancer stem cell |
| spellingShingle | Alejandra I. Ferrer-Diaz Garima Sinha Andrew Petryna Ruth Gonzalez-Bermejo Yannick Kenfack Oluwadamilola Adetayo Shyam A. Patel Anupama Hooda-Nehra Pranela Rameshwar Revealing role of epigenetic modifiers and DNA oxidation in cell-autonomous regulation of Cancer stem cells Cell Communication and Signaling Breast cancer Dormancy Epigenome Resistance Breast cancer Cancer stem cell |
| title | Revealing role of epigenetic modifiers and DNA oxidation in cell-autonomous regulation of Cancer stem cells |
| title_full | Revealing role of epigenetic modifiers and DNA oxidation in cell-autonomous regulation of Cancer stem cells |
| title_fullStr | Revealing role of epigenetic modifiers and DNA oxidation in cell-autonomous regulation of Cancer stem cells |
| title_full_unstemmed | Revealing role of epigenetic modifiers and DNA oxidation in cell-autonomous regulation of Cancer stem cells |
| title_short | Revealing role of epigenetic modifiers and DNA oxidation in cell-autonomous regulation of Cancer stem cells |
| title_sort | revealing role of epigenetic modifiers and dna oxidation in cell autonomous regulation of cancer stem cells |
| topic | Breast cancer Dormancy Epigenome Resistance Breast cancer Cancer stem cell |
| url | https://doi.org/10.1186/s12964-024-01512-1 |
| work_keys_str_mv | AT alejandraiferrerdiaz revealingroleofepigeneticmodifiersanddnaoxidationincellautonomousregulationofcancerstemcells AT garimasinha revealingroleofepigeneticmodifiersanddnaoxidationincellautonomousregulationofcancerstemcells AT andrewpetryna revealingroleofepigeneticmodifiersanddnaoxidationincellautonomousregulationofcancerstemcells AT ruthgonzalezbermejo revealingroleofepigeneticmodifiersanddnaoxidationincellautonomousregulationofcancerstemcells AT yannickkenfack revealingroleofepigeneticmodifiersanddnaoxidationincellautonomousregulationofcancerstemcells AT oluwadamilolaadetayo revealingroleofepigeneticmodifiersanddnaoxidationincellautonomousregulationofcancerstemcells AT shyamapatel revealingroleofepigeneticmodifiersanddnaoxidationincellautonomousregulationofcancerstemcells AT anupamahoodanehra revealingroleofepigeneticmodifiersanddnaoxidationincellautonomousregulationofcancerstemcells AT pranelarameshwar revealingroleofepigeneticmodifiersanddnaoxidationincellautonomousregulationofcancerstemcells |