DNMT1 expression partially dictates 5-Azacytidine sensitivity and correlates with RAS/MEK/ERK activity in gastric cancer cells
Though DNMTs inhibitors were widely used in myelodysplastic syndrome and leukaemia, their application in solid tumours has been limited by low response rate and lack of optimal combination strategies. In gastric cancer (GC), the therapeutic implication of KRAS mutation or MEK/ERK activation for comb...
| Main Authors: | , , , , , , |
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| Format: | Article |
| Language: | English |
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Taylor & Francis Group
2023-12-01
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| Series: | Epigenetics |
| Subjects: | |
| Online Access: | http://dx.doi.org/10.1080/15592294.2023.2254976 |
| _version_ | 1827811418071629824 |
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| author | Zhangqian Chen Lin Zhang Yang Yang Haiming Liu Xiaoyu Kang Yongzhan Nie Daiming Fan |
| author_facet | Zhangqian Chen Lin Zhang Yang Yang Haiming Liu Xiaoyu Kang Yongzhan Nie Daiming Fan |
| author_sort | Zhangqian Chen |
| collection | DOAJ |
| description | Though DNMTs inhibitors were widely used in myelodysplastic syndrome and leukaemia, their application in solid tumours has been limited by low response rate and lack of optimal combination strategies. In gastric cancer (GC), the therapeutic implication of KRAS mutation or MEK/ERK activation for combinational use of DNMTs inhibitors with MEK/ERK inhibitors remains elusive. In this study, stable knockdown of DNMT1 expression by lentiviral transfection led to decreased sensitivity of GC cells to 5-Azacytidine. KRAS knockdown in KRAS mutant GC cells or the MEK/ERK activation by EGF stimulation in GC cells increased DNMT1 expression, while inhibition of MEK/ERK activity by Selumetinib led to decreased DNMT1 expression. 5-Azacytidine treatment, which led to dramatic decline of DNMTs protein levels and increased activity of MEK/ERK pathway, altered the activity of MEK/ERK inhibitor Selumetinib on GC cells. Both RAS-dependent gene expression signature and expression levels of multiple MEK/ERK-dependent genes were correlated with DNMT1 expression in TCGA stomach cancer samples. In conclusion, DNMT1 expression partially dictates 5-Azacytidine sensitivity and correlates with RAS/MEK/ERK activity in GC cells. Combining DNMTs inhibitor with MEK/ERK inhibitor might be a promising strategy for patients with GC. |
| first_indexed | 2024-03-11T23:05:03Z |
| format | Article |
| id | doaj.art-cf65dc01fb1246bf9492b518d01e632f |
| institution | Directory Open Access Journal |
| issn | 1559-2294 1559-2308 |
| language | English |
| last_indexed | 2024-03-11T23:05:03Z |
| publishDate | 2023-12-01 |
| publisher | Taylor & Francis Group |
| record_format | Article |
| series | Epigenetics |
| spelling | doaj.art-cf65dc01fb1246bf9492b518d01e632f2023-09-21T13:23:14ZengTaylor & Francis GroupEpigenetics1559-22941559-23082023-12-0118110.1080/15592294.2023.22549762254976DNMT1 expression partially dictates 5-Azacytidine sensitivity and correlates with RAS/MEK/ERK activity in gastric cancer cellsZhangqian Chen0Lin Zhang1Yang Yang2Haiming Liu3Xiaoyu Kang4Yongzhan Nie5Daiming Fan6Fourth Military Medical UniversityCentral Medical Branch of Chinese PLA General HospitalShaanxi Provincial People’s HospitalBeijing Jiaotong UniversityFourth Military Medical UniversityFourth Military Medical UniversityFourth Military Medical UniversityThough DNMTs inhibitors were widely used in myelodysplastic syndrome and leukaemia, their application in solid tumours has been limited by low response rate and lack of optimal combination strategies. In gastric cancer (GC), the therapeutic implication of KRAS mutation or MEK/ERK activation for combinational use of DNMTs inhibitors with MEK/ERK inhibitors remains elusive. In this study, stable knockdown of DNMT1 expression by lentiviral transfection led to decreased sensitivity of GC cells to 5-Azacytidine. KRAS knockdown in KRAS mutant GC cells or the MEK/ERK activation by EGF stimulation in GC cells increased DNMT1 expression, while inhibition of MEK/ERK activity by Selumetinib led to decreased DNMT1 expression. 5-Azacytidine treatment, which led to dramatic decline of DNMTs protein levels and increased activity of MEK/ERK pathway, altered the activity of MEK/ERK inhibitor Selumetinib on GC cells. Both RAS-dependent gene expression signature and expression levels of multiple MEK/ERK-dependent genes were correlated with DNMT1 expression in TCGA stomach cancer samples. In conclusion, DNMT1 expression partially dictates 5-Azacytidine sensitivity and correlates with RAS/MEK/ERK activity in GC cells. Combining DNMTs inhibitor with MEK/ERK inhibitor might be a promising strategy for patients with GC.http://dx.doi.org/10.1080/15592294.2023.2254976gastric cancerdna methyltransferasemek/erk pathwaytreatment strategy5-azacytidine |
| spellingShingle | Zhangqian Chen Lin Zhang Yang Yang Haiming Liu Xiaoyu Kang Yongzhan Nie Daiming Fan DNMT1 expression partially dictates 5-Azacytidine sensitivity and correlates with RAS/MEK/ERK activity in gastric cancer cells Epigenetics gastric cancer dna methyltransferase mek/erk pathway treatment strategy 5-azacytidine |
| title | DNMT1 expression partially dictates 5-Azacytidine sensitivity and correlates with RAS/MEK/ERK activity in gastric cancer cells |
| title_full | DNMT1 expression partially dictates 5-Azacytidine sensitivity and correlates with RAS/MEK/ERK activity in gastric cancer cells |
| title_fullStr | DNMT1 expression partially dictates 5-Azacytidine sensitivity and correlates with RAS/MEK/ERK activity in gastric cancer cells |
| title_full_unstemmed | DNMT1 expression partially dictates 5-Azacytidine sensitivity and correlates with RAS/MEK/ERK activity in gastric cancer cells |
| title_short | DNMT1 expression partially dictates 5-Azacytidine sensitivity and correlates with RAS/MEK/ERK activity in gastric cancer cells |
| title_sort | dnmt1 expression partially dictates 5 azacytidine sensitivity and correlates with ras mek erk activity in gastric cancer cells |
| topic | gastric cancer dna methyltransferase mek/erk pathway treatment strategy 5-azacytidine |
| url | http://dx.doi.org/10.1080/15592294.2023.2254976 |
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