Histone-acetyl epigenome regulates TGF-β pathway-associated chemoresistance in colorectal cancer
TGF-β signaling pathway has been demonstrated to be closely related to chemoresistance, which is the major cause of recurrence and poor outcome in colorectal cancer (CRC), however, the comprehensive epigenetic landscape that functionally implicates in the regulation of TGF-β pathway-associated chemo...
Saved in:
| Main Authors: | , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2025-01-01
|
| Series: | Translational Oncology |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S1936523324002924 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1846136547842195456 |
|---|---|
| author | Xianglong Tian Guihua Liu Linhua Ji Yi Shen Junjun Gu Lili Wang Jiali Ma Zuguang Xia Xinghua Li |
| author_facet | Xianglong Tian Guihua Liu Linhua Ji Yi Shen Junjun Gu Lili Wang Jiali Ma Zuguang Xia Xinghua Li |
| author_sort | Xianglong Tian |
| collection | DOAJ |
| description | TGF-β signaling pathway has been demonstrated to be closely related to chemoresistance, which is the major cause of recurrence and poor outcome in colorectal cancer (CRC), however, the comprehensive epigenetic landscape that functionally implicates in the regulation of TGF-β pathway-associated chemoresistance has not yet well established in CRC. In our study, chromatin immunoprecipitation sequencing (ChIP-seq) and Western blot were employed to investigate epigenetic modifications for histones in response to TGF-β1 intervene. We found that the activation of the TGF-β pathway was characterized by genome-wide high levels of H3K9ac and H3K18ac. Mechanistically, the activation of the TGF-β signaling pathway leads to the downregulation of the deacetylase HDAC4, resulting in the upregulation of H3K9ac and H3K18ac. Consequently, this cascade induces oxaliplatin chemoresistance in CRC by triggering the anti-apoptotic PI3K/AKT signaling pathway. Our in vivo experiment results confirmed that overexpression of HDAC4 significantly enhances the sensitivity of CRC to oxaliplatin chemotherapy. Moreover, the expression level of HDAC4 was positively correlated with patients’ prognosis in CRC. Our data suggest that histone-acetyl modification demonstrates a crucial role in modulating TGF-β pathway-associated chemoresistance in CRC, and HDAC4 would be a biomarker for prognostic prediction and potential therapeutic target for treatment in CRC. |
| format | Article |
| id | doaj-art-7b5f7c0e3f6e4c7dbb2203c5fbaa4ce3 |
| institution | Kabale University |
| issn | 1936-5233 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Translational Oncology |
| spelling | doaj-art-7b5f7c0e3f6e4c7dbb2203c5fbaa4ce32024-12-09T04:27:00ZengElsevierTranslational Oncology1936-52332025-01-0151102166Histone-acetyl epigenome regulates TGF-β pathway-associated chemoresistance in colorectal cancerXianglong Tian0Guihua Liu1Linhua Ji2Yi Shen3Junjun Gu4Lili Wang5Jiali Ma6Zuguang Xia7Xinghua Li8Department of Gastroenterology, Shanghai Eighth People's Hospital, Xuhui Branch of Shanghai Sixth People's Hospital, 20030, China; Corresponding authors.Department of General Practice, Minhang District Hongqiao Community Health Service Center, Shanghai, 201103, ChinaDepartment of Gastrointestinal Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, ChinaDepartment of Gastroenterology, Shanghai Eighth People's Hospital, Xuhui Branch of Shanghai Sixth People's Hospital, 20030, ChinaDepartment of Gastroenterology, Shanghai Eighth People's Hospital, Xuhui Branch of Shanghai Sixth People's Hospital, 20030, ChinaDepartment of Gastroenterology, Shanghai Eighth People's Hospital, Xuhui Branch of Shanghai Sixth People's Hospital, 20030, ChinaDepartment of Gastroenterology, Tongren Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200336, China; Corresponding authors.Department of Medical Oncology, Fudan University Shanghai Cancer Center, Shanghai, 200032, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China; Corresponding authors.Department of Gastroenterology, Shanghai Eighth People's Hospital, Xuhui Branch of Shanghai Sixth People's Hospital, 20030, China; Corresponding authors.TGF-β signaling pathway has been demonstrated to be closely related to chemoresistance, which is the major cause of recurrence and poor outcome in colorectal cancer (CRC), however, the comprehensive epigenetic landscape that functionally implicates in the regulation of TGF-β pathway-associated chemoresistance has not yet well established in CRC. In our study, chromatin immunoprecipitation sequencing (ChIP-seq) and Western blot were employed to investigate epigenetic modifications for histones in response to TGF-β1 intervene. We found that the activation of the TGF-β pathway was characterized by genome-wide high levels of H3K9ac and H3K18ac. Mechanistically, the activation of the TGF-β signaling pathway leads to the downregulation of the deacetylase HDAC4, resulting in the upregulation of H3K9ac and H3K18ac. Consequently, this cascade induces oxaliplatin chemoresistance in CRC by triggering the anti-apoptotic PI3K/AKT signaling pathway. Our in vivo experiment results confirmed that overexpression of HDAC4 significantly enhances the sensitivity of CRC to oxaliplatin chemotherapy. Moreover, the expression level of HDAC4 was positively correlated with patients’ prognosis in CRC. Our data suggest that histone-acetyl modification demonstrates a crucial role in modulating TGF-β pathway-associated chemoresistance in CRC, and HDAC4 would be a biomarker for prognostic prediction and potential therapeutic target for treatment in CRC.http://www.sciencedirect.com/science/article/pii/S1936523324002924Colorectal cancerTGF-β signaling pathwayepigenetic modificationchemoresistanceHDAC4 |
| spellingShingle | Xianglong Tian Guihua Liu Linhua Ji Yi Shen Junjun Gu Lili Wang Jiali Ma Zuguang Xia Xinghua Li Histone-acetyl epigenome regulates TGF-β pathway-associated chemoresistance in colorectal cancer Translational Oncology Colorectal cancer TGF-β signaling pathway epigenetic modification chemoresistance HDAC4 |
| title | Histone-acetyl epigenome regulates TGF-β pathway-associated chemoresistance in colorectal cancer |
| title_full | Histone-acetyl epigenome regulates TGF-β pathway-associated chemoresistance in colorectal cancer |
| title_fullStr | Histone-acetyl epigenome regulates TGF-β pathway-associated chemoresistance in colorectal cancer |
| title_full_unstemmed | Histone-acetyl epigenome regulates TGF-β pathway-associated chemoresistance in colorectal cancer |
| title_short | Histone-acetyl epigenome regulates TGF-β pathway-associated chemoresistance in colorectal cancer |
| title_sort | histone acetyl epigenome regulates tgf β pathway associated chemoresistance in colorectal cancer |
| topic | Colorectal cancer TGF-β signaling pathway epigenetic modification chemoresistance HDAC4 |
| url | http://www.sciencedirect.com/science/article/pii/S1936523324002924 |
| work_keys_str_mv | AT xianglongtian histoneacetylepigenomeregulatestgfbpathwayassociatedchemoresistanceincolorectalcancer AT guihualiu histoneacetylepigenomeregulatestgfbpathwayassociatedchemoresistanceincolorectalcancer AT linhuaji histoneacetylepigenomeregulatestgfbpathwayassociatedchemoresistanceincolorectalcancer AT yishen histoneacetylepigenomeregulatestgfbpathwayassociatedchemoresistanceincolorectalcancer AT junjungu histoneacetylepigenomeregulatestgfbpathwayassociatedchemoresistanceincolorectalcancer AT liliwang histoneacetylepigenomeregulatestgfbpathwayassociatedchemoresistanceincolorectalcancer AT jialima histoneacetylepigenomeregulatestgfbpathwayassociatedchemoresistanceincolorectalcancer AT zuguangxia histoneacetylepigenomeregulatestgfbpathwayassociatedchemoresistanceincolorectalcancer AT xinghuali histoneacetylepigenomeregulatestgfbpathwayassociatedchemoresistanceincolorectalcancer |