CircRNA-DOPEY2 enhances the chemosensitivity of esophageal cancer cells by inhibiting CPEB4-mediated Mcl-1 translation

Abstract Background Cisplatin-based chemotherapy is a mainstay systematic therapy for advanced esophageal squamous cell carcinoma (ESCC), and cisplatin resistance, which is not uncommon, is the major barrier to improving patient outcomes. Circular RNAs (circRNAs) are novel noncoding RNAs that are im...

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Autores principales:	Zhenchuan Liu, Shaorui Gu, Kaiqin Wu, Lei Li, Chenglai Dong, Wenli Wang, Yongxin Zhou
Formato:	article
Lenguaje:	EN
Publicado:	BMC 2021
Materias:	Circular RNA Esophageal squamous cell carcinoma Cisplatin resistance CPEB4 Mcl-1 Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
Acceso en línea:	https://doaj.org/article/22b284bfe9074813ab745f34e13de7ed
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spelling	oai:doaj.org-article:22b284bfe9074813ab745f34e13de7ed2021-11-21T12:13:22ZCircRNA-DOPEY2 enhances the chemosensitivity of esophageal cancer cells by inhibiting CPEB4-mediated Mcl-1 translation10.1186/s13046-021-02149-51756-9966https://doaj.org/article/22b284bfe9074813ab745f34e13de7ed2021-11-01T00:00:00Zhttps://doi.org/10.1186/s13046-021-02149-5https://doaj.org/toc/1756-9966Abstract Background Cisplatin-based chemotherapy is a mainstay systematic therapy for advanced esophageal squamous cell carcinoma (ESCC), and cisplatin resistance, which is not uncommon, is the major barrier to improving patient outcomes. Circular RNAs (circRNAs) are novel noncoding RNAs that are implicated in cancer progression, but their involvement in modulating cisplatin responsiveness in ESCC remains unknown. Methods Bioinformatics analysis was used to profile and identify the circRNAs involved in cisplatin responsiveness in ESCC. The chemosensitive role of cDOPEY2 was confirmed both in vitro and in vivo. The molecular mechanism of cDOPEY2 was investigated by mass spectrometry, immunoprecipitation, and ubiquitination analyses. Results We report that a novel circRNA (cDOPYE2, hsa_circ_0008078) was markedly downregulated in cisplatin-resistant ESCC cells (ESCC-CR) compared with parental chemosensitive cells. Re-expression of cDOPEY2 substantially enhanced the cell-killing ability of cisplatin by augmenting the apoptotic process in ESCC-CR cells, which was achieved by decreasing the abundance of the antiapoptotic protein Mcl-1. Mechanistically, we showed that cDOPEY2 acted as a protein scaffold to enhance the interaction between the cytoplasmic polyadenylation element binding protein (CPEB4) and the E3 ligase TRIM25, which in turn facilitated the ubiquitination and degradation of CPEB4. The increased Mcl-1 expression in ESCC-CR cells was dependent on the binding of CPEB4 to its untranslated mRNA, and depletion of CPEB4 mediated by cDOPEY2 reversed this effect. Rescue experiments confirmed that the critical role of cDOPEY2 in maintaining cisplatin sensitivity was dependent on the depletion of CEPB4 and its downstream target Mcl-1. Clinical and in vivo data further corroborated the significant relevance of cDOPEY2 to cisplatin responsiveness in ESCC. Conclusions We provide evidence that cDOPEY2 inhibits CPEB4-mediated Mcl-1 translation by promoting the ubiquitination and degradation of CPEB4 to alleviate cisplatin resistance, indicating that cDOPEY2 may serve as a valuable biomarker and potential therapeutic target in ESCC.Zhenchuan LiuShaorui GuKaiqin WuLei LiChenglai DongWenli WangYongxin ZhouBMCarticleCircular RNAEsophageal squamous cell carcinomaCisplatin resistanceCPEB4Mcl-1Neoplasms. Tumors. Oncology. Including cancer and carcinogensRC254-282ENJournal of Experimental & Clinical Cancer Research, Vol 40, Iss 1, Pp 1-17 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Circular RNA Esophageal squamous cell carcinoma Cisplatin resistance CPEB4 Mcl-1 Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
spellingShingle	Circular RNA Esophageal squamous cell carcinoma Cisplatin resistance CPEB4 Mcl-1 Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282 Zhenchuan Liu Shaorui Gu Kaiqin Wu Lei Li Chenglai Dong Wenli Wang Yongxin Zhou CircRNA-DOPEY2 enhances the chemosensitivity of esophageal cancer cells by inhibiting CPEB4-mediated Mcl-1 translation
description	Abstract Background Cisplatin-based chemotherapy is a mainstay systematic therapy for advanced esophageal squamous cell carcinoma (ESCC), and cisplatin resistance, which is not uncommon, is the major barrier to improving patient outcomes. Circular RNAs (circRNAs) are novel noncoding RNAs that are implicated in cancer progression, but their involvement in modulating cisplatin responsiveness in ESCC remains unknown. Methods Bioinformatics analysis was used to profile and identify the circRNAs involved in cisplatin responsiveness in ESCC. The chemosensitive role of cDOPEY2 was confirmed both in vitro and in vivo. The molecular mechanism of cDOPEY2 was investigated by mass spectrometry, immunoprecipitation, and ubiquitination analyses. Results We report that a novel circRNA (cDOPYE2, hsa_circ_0008078) was markedly downregulated in cisplatin-resistant ESCC cells (ESCC-CR) compared with parental chemosensitive cells. Re-expression of cDOPEY2 substantially enhanced the cell-killing ability of cisplatin by augmenting the apoptotic process in ESCC-CR cells, which was achieved by decreasing the abundance of the antiapoptotic protein Mcl-1. Mechanistically, we showed that cDOPEY2 acted as a protein scaffold to enhance the interaction between the cytoplasmic polyadenylation element binding protein (CPEB4) and the E3 ligase TRIM25, which in turn facilitated the ubiquitination and degradation of CPEB4. The increased Mcl-1 expression in ESCC-CR cells was dependent on the binding of CPEB4 to its untranslated mRNA, and depletion of CPEB4 mediated by cDOPEY2 reversed this effect. Rescue experiments confirmed that the critical role of cDOPEY2 in maintaining cisplatin sensitivity was dependent on the depletion of CEPB4 and its downstream target Mcl-1. Clinical and in vivo data further corroborated the significant relevance of cDOPEY2 to cisplatin responsiveness in ESCC. Conclusions We provide evidence that cDOPEY2 inhibits CPEB4-mediated Mcl-1 translation by promoting the ubiquitination and degradation of CPEB4 to alleviate cisplatin resistance, indicating that cDOPEY2 may serve as a valuable biomarker and potential therapeutic target in ESCC.
format	article
author	Zhenchuan Liu Shaorui Gu Kaiqin Wu Lei Li Chenglai Dong Wenli Wang Yongxin Zhou
author_facet	Zhenchuan Liu Shaorui Gu Kaiqin Wu Lei Li Chenglai Dong Wenli Wang Yongxin Zhou
author_sort	Zhenchuan Liu
title	CircRNA-DOPEY2 enhances the chemosensitivity of esophageal cancer cells by inhibiting CPEB4-mediated Mcl-1 translation
title_short	CircRNA-DOPEY2 enhances the chemosensitivity of esophageal cancer cells by inhibiting CPEB4-mediated Mcl-1 translation
title_full	CircRNA-DOPEY2 enhances the chemosensitivity of esophageal cancer cells by inhibiting CPEB4-mediated Mcl-1 translation
title_fullStr	CircRNA-DOPEY2 enhances the chemosensitivity of esophageal cancer cells by inhibiting CPEB4-mediated Mcl-1 translation
title_full_unstemmed	CircRNA-DOPEY2 enhances the chemosensitivity of esophageal cancer cells by inhibiting CPEB4-mediated Mcl-1 translation
title_sort	circrna-dopey2 enhances the chemosensitivity of esophageal cancer cells by inhibiting cpeb4-mediated mcl-1 translation
publisher	BMC
publishDate	2021
url	https://doaj.org/article/22b284bfe9074813ab745f34e13de7ed
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CircRNA-DOPEY2 enhances the chemosensitivity of esophageal cancer cells by inhibiting CPEB4-mediated Mcl-1 translation

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