Metabolic perturbation of epigenome by inhibiting -adenosylhomocysteine hydrolase elicits senescence through DNA damage response in hepatoma cells
Cellular senescence is a key physiological barrier against tumor and represents an option for therapeutic intervention. One pivotal intracellular stimulus causing senescence is DNA damage response, while the senescence-associated heterochromatin in cancer limits the strength of the DNA damage respon...
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| Format: | Article |
| Language: | English |
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SAGE Publishing
2017-04-01
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| Series: | Tumor Biology |
| Online Access: | https://doi.org/10.1177/1010428317699117 |
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| author | Guozhen Wu Ning Wang Ying Luo Yanyan Zhang Peng Wang Zhengyan Zhu Yingtang Gao Zhi Du Bin Yang |
| author_facet | Guozhen Wu Ning Wang Ying Luo Yanyan Zhang Peng Wang Zhengyan Zhu Yingtang Gao Zhi Du Bin Yang |
| author_sort | Guozhen Wu |
| collection | DOAJ |
| description | Cellular senescence is a key physiological barrier against tumor and represents an option for therapeutic intervention. One pivotal intracellular stimulus causing senescence is DNA damage response, while the senescence-associated heterochromatin in cancer limits the strength of the DNA damage response to endogenous genotoxic stress or DNA-damaging agents. Therefore, targeting the maintenance of compacted chromatin in cancer cells represents an optional intervention to improve the therapeutic efficacy in cancer treatment. Given a crosstalk between methionine cycle and histone methylation, we hypothesize that pharmacologically disrupting methylation potential, defined as the ratio of cellular S -adenosylmethionine to S -adenosylhomocysteine, could affect the chromatin structures in cancer cells and thus enhance their sensitivity to DNA damage response signaling. Our results showed that 3-deazaneplanocin A, a chemical inhibitor of S -adenosylhomocysteine hydrolase, elicited a typical cellular senescence in hepatoma cells. Therapy-induced senescence by 3-deazaneplanocin A was mediated through p53–p21 pathway and triggered by enhanced ataxia-telangiectasia mutated activation related to chromatin changes. In conclusion, our study demonstrated that metabolic perturbation of chromatin status in oncogene-activated cancers could be an optional intervention to sensitize DNA damage response signaling. |
| format | Article |
| id | doaj-art-3d154460b73f4cddb39a17e506e71d70 |
| institution | Kabale University |
| issn | 1423-0380 |
| language | English |
| publishDate | 2017-04-01 |
| publisher | SAGE Publishing |
| record_format | Article |
| series | Tumor Biology |
| spelling | doaj-art-3d154460b73f4cddb39a17e506e71d702025-08-20T03:33:15ZengSAGE PublishingTumor Biology1423-03802017-04-013910.1177/1010428317699117Metabolic perturbation of epigenome by inhibiting -adenosylhomocysteine hydrolase elicits senescence through DNA damage response in hepatoma cellsGuozhen Wu0Ning Wang1Ying Luo2Yanyan Zhang3Peng Wang4Zhengyan Zhu5Yingtang Gao6Zhi Du7Bin Yang8Department of Hepatobiliary Surgery, The Third Central Hospital of Tianjin, Tianjin Medical University, Tianjin, ChinaKey Laboratory of Hormones and Development (Ministry of Health), Tianjin Key Laboratory of Metabolic Diseases, Tianjin Metabolic Diseases Hospital & Tianjin Institute of Endocrinology, Tianjin Medical University, Tianjin, ChinaInstitute of Hepatobiliary Disease, The Third Central Hospital of Tianjin, Tianjin Medical University, Tianjin, ChinaKey Laboratory of Artificial Cells, The Third Central Hospital of Tianjin, Tianjin Medical University, Tianjin, ChinaInstitute of Hepatobiliary Disease, The Third Central Hospital of Tianjin, Tianjin Medical University, Tianjin, ChinaInstitute of Hepatobiliary Disease, The Third Central Hospital of Tianjin, Tianjin Medical University, Tianjin, ChinaInstitute of Hepatobiliary Disease, The Third Central Hospital of Tianjin, Tianjin Medical University, Tianjin, ChinaInstitute of Hepatobiliary Disease, The Third Central Hospital of Tianjin, Tianjin Medical University, Tianjin, ChinaInstitute of Hepatobiliary Disease, The Third Central Hospital of Tianjin, Tianjin Medical University, Tianjin, ChinaCellular senescence is a key physiological barrier against tumor and represents an option for therapeutic intervention. One pivotal intracellular stimulus causing senescence is DNA damage response, while the senescence-associated heterochromatin in cancer limits the strength of the DNA damage response to endogenous genotoxic stress or DNA-damaging agents. Therefore, targeting the maintenance of compacted chromatin in cancer cells represents an optional intervention to improve the therapeutic efficacy in cancer treatment. Given a crosstalk between methionine cycle and histone methylation, we hypothesize that pharmacologically disrupting methylation potential, defined as the ratio of cellular S -adenosylmethionine to S -adenosylhomocysteine, could affect the chromatin structures in cancer cells and thus enhance their sensitivity to DNA damage response signaling. Our results showed that 3-deazaneplanocin A, a chemical inhibitor of S -adenosylhomocysteine hydrolase, elicited a typical cellular senescence in hepatoma cells. Therapy-induced senescence by 3-deazaneplanocin A was mediated through p53–p21 pathway and triggered by enhanced ataxia-telangiectasia mutated activation related to chromatin changes. In conclusion, our study demonstrated that metabolic perturbation of chromatin status in oncogene-activated cancers could be an optional intervention to sensitize DNA damage response signaling.https://doi.org/10.1177/1010428317699117 |
| spellingShingle | Guozhen Wu Ning Wang Ying Luo Yanyan Zhang Peng Wang Zhengyan Zhu Yingtang Gao Zhi Du Bin Yang Metabolic perturbation of epigenome by inhibiting -adenosylhomocysteine hydrolase elicits senescence through DNA damage response in hepatoma cells Tumor Biology |
| title | Metabolic perturbation of epigenome by inhibiting -adenosylhomocysteine hydrolase elicits senescence through DNA damage response in hepatoma cells |
| title_full | Metabolic perturbation of epigenome by inhibiting -adenosylhomocysteine hydrolase elicits senescence through DNA damage response in hepatoma cells |
| title_fullStr | Metabolic perturbation of epigenome by inhibiting -adenosylhomocysteine hydrolase elicits senescence through DNA damage response in hepatoma cells |
| title_full_unstemmed | Metabolic perturbation of epigenome by inhibiting -adenosylhomocysteine hydrolase elicits senescence through DNA damage response in hepatoma cells |
| title_short | Metabolic perturbation of epigenome by inhibiting -adenosylhomocysteine hydrolase elicits senescence through DNA damage response in hepatoma cells |
| title_sort | metabolic perturbation of epigenome by inhibiting adenosylhomocysteine hydrolase elicits senescence through dna damage response in hepatoma cells |
| url | https://doi.org/10.1177/1010428317699117 |
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