A methyltransferase‐like 14/miR‐99a‐5p/tribble 2 positive feedback circuit promotes cancer stem cell persistence and radioresistance via histone deacetylase 2‐mediated epigenetic modulation in esophageal squamous cell carcinoma

Abstract Background Esophageal squamous cell carcinoma (ESCC) is a highly aggressive and treatment‐resistant tumor. The biological implications and molecular mechanism of cancer stem‐like cells (CSCs) in ESCC, which contribute to therapeutic resistance such as radioresistance, remain elusive. Method...

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Autores principales:	Zhenchuan Liu, Kaiqing Wu, Shaorui Gu, Wenli Wang, Shiliang Xie, Tiancheng Lu, Lei Li, Chenglai Dong, Xishi Wang, Yongxin Zhou
Formato:	article
Lenguaje:	EN
Publicado:	Wiley 2021
Materias:	cancer stem‐like cells esophageal squamous cell carcinoma positive feedback loop radioresistance Medicine (General) R5-920
Acceso en línea:	https://doaj.org/article/2503bc6e99a14e1f92f41f05e9c1cdb3
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spelling	oai:doaj.org-article:2503bc6e99a14e1f92f41f05e9c1cdb32021-11-11T12:06:40ZA methyltransferase‐like 14/miR‐99a‐5p/tribble 2 positive feedback circuit promotes cancer stem cell persistence and radioresistance via histone deacetylase 2‐mediated epigenetic modulation in esophageal squamous cell carcinoma2001-132610.1002/ctm2.545https://doaj.org/article/2503bc6e99a14e1f92f41f05e9c1cdb32021-09-01T00:00:00Zhttps://doi.org/10.1002/ctm2.545https://doaj.org/toc/2001-1326Abstract Background Esophageal squamous cell carcinoma (ESCC) is a highly aggressive and treatment‐resistant tumor. The biological implications and molecular mechanism of cancer stem‐like cells (CSCs) in ESCC, which contribute to therapeutic resistance such as radioresistance, remain elusive. Methods Quantitative real‐time polymerase chain reaction, western blotting, immunohistochemistry, and in situ hybridization assays were used to detect methyltransferase‐like 14 miR‐99a‐5p tribble 2 (METTL14/miR‐99a‐5p/TRIB2) expression in ESCC. The biological functions of METTL14/miR‐99a‐5p/TRIB2 were demonstrated in vitro and in vivo. Mass spectrum analysis was used to identify the downstream proteins regulated by TRIB2. Chromatin immunoprecipitation (IP), IP, N6‐methyladenosine (m6A)‐RNA IP, luciferase reporter, and ubiquitination assays were employed to explore the molecular mechanisms underlying this feedback circuit and its downstream pathways. Results We found that miR‐99a‐5p was significantly decreased in ESCC. miR‐99a‐5p inhibited CSCs persistence and the radioresistance of ESCC cells, and miR‐99a‐5p downregulation predicted an unfavorable prognosis of ESCC patients. Mechanically, we unveiled a METTL14‐miR‐99a‐5p‐TRIB2 positive feedback loop that enhances CSC properties and radioresistance of ESCC cells. METTL14, an m6A RNA methyltransferase downregulated in ESCC, suppresses TRIB2 expression via miR‐99a‐5p‐mediated degradation of TRIB2 mRNA by targeting its 3′ untranslated region, whereas TRIB2 induces ubiquitin‐mediated proteasomal degradation of METTL14 in a COP1‐dependent manner. METTL14 upregulates miR‐99a‐5p by modulating m6A‐mediated, DiGeorge critical region 8‐dependent pri‐mir‐99a processing. Hyperactivation of TRIB2 resulting from this positive circuit was closely correlated with radioresistance and CSC characteristics. Furthermore, TRIB2 activates HDAC2 and subsequently induces p21 epigenetic repression through Akt/mTOR/S6K1 signaling pathway activation. Pharmacologic inhibition of HDAC2 effectively attenuates the TRIB2‐mediated effect both in vitro and in patient‐derived xenograft models. Conclusion Our data highlight the presence of the METTL14/miR‐99a‐5p/TRIB2 axis and show that it is positively associated with CSC characteristics and radioresistance of ESCC, suggesting potential therapeutic targets for ESCC treatment.Zhenchuan LiuKaiqing WuShaorui GuWenli WangShiliang XieTiancheng LuLei LiChenglai DongXishi WangYongxin ZhouWileyarticlecancer stem‐like cellsesophageal squamous cell carcinomapositive feedback loopradioresistanceMedicine (General)R5-920ENClinical and Translational Medicine, Vol 11, Iss 9, Pp n/a-n/a (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	cancer stem‐like cells esophageal squamous cell carcinoma positive feedback loop radioresistance Medicine (General) R5-920
spellingShingle	cancer stem‐like cells esophageal squamous cell carcinoma positive feedback loop radioresistance Medicine (General) R5-920 Zhenchuan Liu Kaiqing Wu Shaorui Gu Wenli Wang Shiliang Xie Tiancheng Lu Lei Li Chenglai Dong Xishi Wang Yongxin Zhou A methyltransferase‐like 14/miR‐99a‐5p/tribble 2 positive feedback circuit promotes cancer stem cell persistence and radioresistance via histone deacetylase 2‐mediated epigenetic modulation in esophageal squamous cell carcinoma
description	Abstract Background Esophageal squamous cell carcinoma (ESCC) is a highly aggressive and treatment‐resistant tumor. The biological implications and molecular mechanism of cancer stem‐like cells (CSCs) in ESCC, which contribute to therapeutic resistance such as radioresistance, remain elusive. Methods Quantitative real‐time polymerase chain reaction, western blotting, immunohistochemistry, and in situ hybridization assays were used to detect methyltransferase‐like 14 miR‐99a‐5p tribble 2 (METTL14/miR‐99a‐5p/TRIB2) expression in ESCC. The biological functions of METTL14/miR‐99a‐5p/TRIB2 were demonstrated in vitro and in vivo. Mass spectrum analysis was used to identify the downstream proteins regulated by TRIB2. Chromatin immunoprecipitation (IP), IP, N6‐methyladenosine (m6A)‐RNA IP, luciferase reporter, and ubiquitination assays were employed to explore the molecular mechanisms underlying this feedback circuit and its downstream pathways. Results We found that miR‐99a‐5p was significantly decreased in ESCC. miR‐99a‐5p inhibited CSCs persistence and the radioresistance of ESCC cells, and miR‐99a‐5p downregulation predicted an unfavorable prognosis of ESCC patients. Mechanically, we unveiled a METTL14‐miR‐99a‐5p‐TRIB2 positive feedback loop that enhances CSC properties and radioresistance of ESCC cells. METTL14, an m6A RNA methyltransferase downregulated in ESCC, suppresses TRIB2 expression via miR‐99a‐5p‐mediated degradation of TRIB2 mRNA by targeting its 3′ untranslated region, whereas TRIB2 induces ubiquitin‐mediated proteasomal degradation of METTL14 in a COP1‐dependent manner. METTL14 upregulates miR‐99a‐5p by modulating m6A‐mediated, DiGeorge critical region 8‐dependent pri‐mir‐99a processing. Hyperactivation of TRIB2 resulting from this positive circuit was closely correlated with radioresistance and CSC characteristics. Furthermore, TRIB2 activates HDAC2 and subsequently induces p21 epigenetic repression through Akt/mTOR/S6K1 signaling pathway activation. Pharmacologic inhibition of HDAC2 effectively attenuates the TRIB2‐mediated effect both in vitro and in patient‐derived xenograft models. Conclusion Our data highlight the presence of the METTL14/miR‐99a‐5p/TRIB2 axis and show that it is positively associated with CSC characteristics and radioresistance of ESCC, suggesting potential therapeutic targets for ESCC treatment.
format	article
author	Zhenchuan Liu Kaiqing Wu Shaorui Gu Wenli Wang Shiliang Xie Tiancheng Lu Lei Li Chenglai Dong Xishi Wang Yongxin Zhou
author_facet	Zhenchuan Liu Kaiqing Wu Shaorui Gu Wenli Wang Shiliang Xie Tiancheng Lu Lei Li Chenglai Dong Xishi Wang Yongxin Zhou
author_sort	Zhenchuan Liu
title	A methyltransferase‐like 14/miR‐99a‐5p/tribble 2 positive feedback circuit promotes cancer stem cell persistence and radioresistance via histone deacetylase 2‐mediated epigenetic modulation in esophageal squamous cell carcinoma
title_short	A methyltransferase‐like 14/miR‐99a‐5p/tribble 2 positive feedback circuit promotes cancer stem cell persistence and radioresistance via histone deacetylase 2‐mediated epigenetic modulation in esophageal squamous cell carcinoma
title_full	A methyltransferase‐like 14/miR‐99a‐5p/tribble 2 positive feedback circuit promotes cancer stem cell persistence and radioresistance via histone deacetylase 2‐mediated epigenetic modulation in esophageal squamous cell carcinoma
title_fullStr	A methyltransferase‐like 14/miR‐99a‐5p/tribble 2 positive feedback circuit promotes cancer stem cell persistence and radioresistance via histone deacetylase 2‐mediated epigenetic modulation in esophageal squamous cell carcinoma
title_full_unstemmed	A methyltransferase‐like 14/miR‐99a‐5p/tribble 2 positive feedback circuit promotes cancer stem cell persistence and radioresistance via histone deacetylase 2‐mediated epigenetic modulation in esophageal squamous cell carcinoma
title_sort	methyltransferase‐like 14/mir‐99a‐5p/tribble 2 positive feedback circuit promotes cancer stem cell persistence and radioresistance via histone deacetylase 2‐mediated epigenetic modulation in esophageal squamous cell carcinoma
publisher	Wiley
publishDate	2021
url	https://doaj.org/article/2503bc6e99a14e1f92f41f05e9c1cdb3
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A methyltransferase‐like 14/miR‐99a‐5p/tribble 2 positive feedback circuit promotes cancer stem cell persistence and radioresistance via histone deacetylase 2‐mediated epigenetic modulation in esophageal squamous cell carcinoma

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