Epigenetic activation of the elongator complex sensitizes gallbladder cancer to gemcitabine therapy

Abstract Background Gallbladder cancer (GBC) is known for its high malignancy and multidrug resistance. Previously, we uncovered that impaired integrity and stability of the elongator complex leads to GBC chemotherapy resistance, but whether its restoration can be an efficient therapeutic strategy f...

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Autores principales:	Sunwang Xu, Cen Jiang, Ruirong Lin, Xiaopeng Wang, Xiaoqiang Hu, Wei Chen, Xiangjin Chen, Tao Chen
Formato:	article
Lenguaje:	EN
Publicado:	BMC 2021
Materias:	Gallbladder cancer Elongator complex DNA methylation Gemcitabine Decitabine Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
Acceso en línea:	https://doaj.org/article/6e5dfc5d99824e50897f13ed8078313d
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spelling	oai:doaj.org-article:6e5dfc5d99824e50897f13ed8078313d2021-11-28T12:13:45ZEpigenetic activation of the elongator complex sensitizes gallbladder cancer to gemcitabine therapy10.1186/s13046-021-02186-01756-9966https://doaj.org/article/6e5dfc5d99824e50897f13ed8078313d2021-11-01T00:00:00Zhttps://doi.org/10.1186/s13046-021-02186-0https://doaj.org/toc/1756-9966Abstract Background Gallbladder cancer (GBC) is known for its high malignancy and multidrug resistance. Previously, we uncovered that impaired integrity and stability of the elongator complex leads to GBC chemotherapy resistance, but whether its restoration can be an efficient therapeutic strategy for GBC remains unknown. Methods RT-qPCR, MS-qPCR and ChIP-qPCR were used to evaluate the direct association between ELP5 transcription and DNA methylation in tumour and non-tumour tissues of GBC. EMSA, chromatin accessibility assays, and luciferase assays were utilized to analysis the DNA methylation in interfering PAX5-DNA interactions. The functional experiments in vitro and in vivo were performed to investigate the effects of DNA demethylating agent decitabine (DAC) on the transcription activation of elongator complex and the enhanced sensitivity of gemcitabine in GBC cells. Tissue microarray contains GBC tumour tissues was used to evaluate the association between the expression of ELP5, DNMT3A and PAX5. Results We demonstrated that transcriptional repression of ELP5 in GBC was highly correlated with hypermethylation of the promoter. Mechanistically, epigenetic analysis revealed that DNA methyltransferase DNMT3A-catalysed hypermethylation blocked transcription factor PAX5 activation of ELP5 by disrupting PAX5-DNA interaction, resulting in repressed ELP5 transcription. Pharmacologically, the DNA demethylating agent DAC eliminated the hypermethylated CpG dinucleotides in the ELP5 promoter and then facilitated PAX5 binding and reactivated ELP5 transcription, leading to the enhanced function of the elongator complex. To target this mechanism, we employed a sequential combination therapy of DAC and gemcitabine to sensitize GBC cells to gemcitabine-therapy through epigenetic activation of the elongator complex. Conclusions Our findings suggest that ELP5 expression in GBC is controlled by DNA methylation-sensitive induction of PAX5. The sequential combination therapy of DAC and gemcitabine could be an efficient therapeutic strategy to overcome chemotherapy resistance in GBC.Sunwang XuCen JiangRuirong LinXiaopeng WangXiaoqiang HuWei ChenXiangjin ChenTao ChenBMCarticleGallbladder cancerElongator complexDNA methylationGemcitabineDecitabineNeoplasms. Tumors. Oncology. Including cancer and carcinogensRC254-282ENJournal of Experimental & Clinical Cancer Research, Vol 40, Iss 1, Pp 1-16 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Gallbladder cancer Elongator complex DNA methylation Gemcitabine Decitabine Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
spellingShingle	Gallbladder cancer Elongator complex DNA methylation Gemcitabine Decitabine Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282 Sunwang Xu Cen Jiang Ruirong Lin Xiaopeng Wang Xiaoqiang Hu Wei Chen Xiangjin Chen Tao Chen Epigenetic activation of the elongator complex sensitizes gallbladder cancer to gemcitabine therapy
description	Abstract Background Gallbladder cancer (GBC) is known for its high malignancy and multidrug resistance. Previously, we uncovered that impaired integrity and stability of the elongator complex leads to GBC chemotherapy resistance, but whether its restoration can be an efficient therapeutic strategy for GBC remains unknown. Methods RT-qPCR, MS-qPCR and ChIP-qPCR were used to evaluate the direct association between ELP5 transcription and DNA methylation in tumour and non-tumour tissues of GBC. EMSA, chromatin accessibility assays, and luciferase assays were utilized to analysis the DNA methylation in interfering PAX5-DNA interactions. The functional experiments in vitro and in vivo were performed to investigate the effects of DNA demethylating agent decitabine (DAC) on the transcription activation of elongator complex and the enhanced sensitivity of gemcitabine in GBC cells. Tissue microarray contains GBC tumour tissues was used to evaluate the association between the expression of ELP5, DNMT3A and PAX5. Results We demonstrated that transcriptional repression of ELP5 in GBC was highly correlated with hypermethylation of the promoter. Mechanistically, epigenetic analysis revealed that DNA methyltransferase DNMT3A-catalysed hypermethylation blocked transcription factor PAX5 activation of ELP5 by disrupting PAX5-DNA interaction, resulting in repressed ELP5 transcription. Pharmacologically, the DNA demethylating agent DAC eliminated the hypermethylated CpG dinucleotides in the ELP5 promoter and then facilitated PAX5 binding and reactivated ELP5 transcription, leading to the enhanced function of the elongator complex. To target this mechanism, we employed a sequential combination therapy of DAC and gemcitabine to sensitize GBC cells to gemcitabine-therapy through epigenetic activation of the elongator complex. Conclusions Our findings suggest that ELP5 expression in GBC is controlled by DNA methylation-sensitive induction of PAX5. The sequential combination therapy of DAC and gemcitabine could be an efficient therapeutic strategy to overcome chemotherapy resistance in GBC.
format	article
author	Sunwang Xu Cen Jiang Ruirong Lin Xiaopeng Wang Xiaoqiang Hu Wei Chen Xiangjin Chen Tao Chen
author_facet	Sunwang Xu Cen Jiang Ruirong Lin Xiaopeng Wang Xiaoqiang Hu Wei Chen Xiangjin Chen Tao Chen
author_sort	Sunwang Xu
title	Epigenetic activation of the elongator complex sensitizes gallbladder cancer to gemcitabine therapy
title_short	Epigenetic activation of the elongator complex sensitizes gallbladder cancer to gemcitabine therapy
title_full	Epigenetic activation of the elongator complex sensitizes gallbladder cancer to gemcitabine therapy
title_fullStr	Epigenetic activation of the elongator complex sensitizes gallbladder cancer to gemcitabine therapy
title_full_unstemmed	Epigenetic activation of the elongator complex sensitizes gallbladder cancer to gemcitabine therapy
title_sort	epigenetic activation of the elongator complex sensitizes gallbladder cancer to gemcitabine therapy
publisher	BMC
publishDate	2021
url	https://doaj.org/article/6e5dfc5d99824e50897f13ed8078313d
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_version_	1718408145948114944

Epigenetic activation of the elongator complex sensitizes gallbladder cancer to gemcitabine therapy

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