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The Deubiquitinase USP39 Promotes ESCC Tumorigenesis Through Pre-mRNA Splicing of the mTORC2 Component Rictor

Spliceosomes are large RNA-protein molecular complexes which mediate splicing of pre-mRNA in eukaryotic cells. Their function is frequently altered in cancer, providing opportunities for novel therapeutic approaches. The ubiquitin specific protease 39 (USP39) is a highly conserved deubiquitylation f...

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Autores principales: Zhao, Yuan, Geng, Huiwu, Liu, Gang, Ji, Qiang, Cheng, Xiaomin, Li, Xinying, Liu, Wei, Thorne, Rick F., Zhang, Renquan, Liu, Xiaoying
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8189149/
https://www.ncbi.nlm.nih.gov/pubmed/34123832
http://dx.doi.org/10.3389/fonc.2021.667495
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author Zhao, Yuan
Geng, Huiwu
Liu, Gang
Ji, Qiang
Cheng, Xiaomin
Li, Xinying
Liu, Wei
Thorne, Rick F.
Zhang, Renquan
Liu, Xiaoying
author_facet Zhao, Yuan
Geng, Huiwu
Liu, Gang
Ji, Qiang
Cheng, Xiaomin
Li, Xinying
Liu, Wei
Thorne, Rick F.
Zhang, Renquan
Liu, Xiaoying
author_sort Zhao, Yuan
collection PubMed
description Spliceosomes are large RNA-protein molecular complexes which mediate splicing of pre-mRNA in eukaryotic cells. Their function is frequently altered in cancer, providing opportunities for novel therapeutic approaches. The ubiquitin specific protease 39 (USP39) is a highly conserved deubiquitylation family member that plays an essential role in pre-mRNA splicing where it serves to assemble the mature spliceosome complex. Previous studies have reported that USP39 acts in an oncogenic manner where it contributes to cancer progression and predicts poor prognosis in various human tumor types. Here we report that USP39 is differentially upregulated in human esophageal squamous cell carcinoma (ESCC) and its expression is significantly associated with clinicopathological characteristics including differentiation status and TNM stage. We found the USP39 upregulation was maintained in ESCC cell lines where it functioned to promote cancer cell growth in vitro and in xenografts. RNA-seq analyses identified that mTOR pathway activation was affected by shRNA-mediated silencing of USP39. Subsequent biochemical analyses demonstrated that USP39 regulates the activity of mTORC2 by selectively enhancing the splicing and maturation of Rictor mRNA, although not other key mTORC components. Together, our report proposes USP39 as a biomarker and oncogenic factor in ESCC, with a potential for targeting the USP39/mTOR2/Rictor axis as a therapeutic strategy. Furthermore, our study adds ESCC to the list of cancers where USP39 contributes to tumorigenesis and progression.
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spelling pubmed-81891492021-06-10 The Deubiquitinase USP39 Promotes ESCC Tumorigenesis Through Pre-mRNA Splicing of the mTORC2 Component Rictor Zhao, Yuan Geng, Huiwu Liu, Gang Ji, Qiang Cheng, Xiaomin Li, Xinying Liu, Wei Thorne, Rick F. Zhang, Renquan Liu, Xiaoying Front Oncol Oncology Spliceosomes are large RNA-protein molecular complexes which mediate splicing of pre-mRNA in eukaryotic cells. Their function is frequently altered in cancer, providing opportunities for novel therapeutic approaches. The ubiquitin specific protease 39 (USP39) is a highly conserved deubiquitylation family member that plays an essential role in pre-mRNA splicing where it serves to assemble the mature spliceosome complex. Previous studies have reported that USP39 acts in an oncogenic manner where it contributes to cancer progression and predicts poor prognosis in various human tumor types. Here we report that USP39 is differentially upregulated in human esophageal squamous cell carcinoma (ESCC) and its expression is significantly associated with clinicopathological characteristics including differentiation status and TNM stage. We found the USP39 upregulation was maintained in ESCC cell lines where it functioned to promote cancer cell growth in vitro and in xenografts. RNA-seq analyses identified that mTOR pathway activation was affected by shRNA-mediated silencing of USP39. Subsequent biochemical analyses demonstrated that USP39 regulates the activity of mTORC2 by selectively enhancing the splicing and maturation of Rictor mRNA, although not other key mTORC components. Together, our report proposes USP39 as a biomarker and oncogenic factor in ESCC, with a potential for targeting the USP39/mTOR2/Rictor axis as a therapeutic strategy. Furthermore, our study adds ESCC to the list of cancers where USP39 contributes to tumorigenesis and progression. Frontiers Media S.A. 2021-05-26 /pmc/articles/PMC8189149/ /pubmed/34123832 http://dx.doi.org/10.3389/fonc.2021.667495 Text en Copyright © 2021 Zhao, Geng, Liu, Ji, Cheng, Li, Liu, Thorne, Zhang and Liu https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Oncology
Zhao, Yuan
Geng, Huiwu
Liu, Gang
Ji, Qiang
Cheng, Xiaomin
Li, Xinying
Liu, Wei
Thorne, Rick F.
Zhang, Renquan
Liu, Xiaoying
The Deubiquitinase USP39 Promotes ESCC Tumorigenesis Through Pre-mRNA Splicing of the mTORC2 Component Rictor
title The Deubiquitinase USP39 Promotes ESCC Tumorigenesis Through Pre-mRNA Splicing of the mTORC2 Component Rictor
title_full The Deubiquitinase USP39 Promotes ESCC Tumorigenesis Through Pre-mRNA Splicing of the mTORC2 Component Rictor
title_fullStr The Deubiquitinase USP39 Promotes ESCC Tumorigenesis Through Pre-mRNA Splicing of the mTORC2 Component Rictor
title_full_unstemmed The Deubiquitinase USP39 Promotes ESCC Tumorigenesis Through Pre-mRNA Splicing of the mTORC2 Component Rictor
title_short The Deubiquitinase USP39 Promotes ESCC Tumorigenesis Through Pre-mRNA Splicing of the mTORC2 Component Rictor
title_sort deubiquitinase usp39 promotes escc tumorigenesis through pre-mrna splicing of the mtorc2 component rictor
topic Oncology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8189149/
https://www.ncbi.nlm.nih.gov/pubmed/34123832
http://dx.doi.org/10.3389/fonc.2021.667495
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