The Deubiquitinase USP39 Promotes ESCC Tumorigenesis Through Pre-mRNA Splicing of the mTORC2 Component Rictor.
The Deubiquitinase USP39 Promotes ESCC Tumorigenesis Through Pre-mRNA Splicing of the mTORC2 Component Rictor.
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去泛素酶 USP39 通过 mTORC2 组分 Rictor 的前 mRNA 剪接促进 ESCC 肿瘤发生
DOI：
10.3389/fonc.2021.667495
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发表时间：
2021
影响因子：
4.7
通讯作者：
Liu X
中科院分区：
文献类型：
--
作者：
Zhao Y;Geng H;Liu G;Ji Q;Cheng X;Li X;Liu W;Thorne RF;Zhang R;Liu X
剪接体是大的RNA-蛋白质分子复合体，介导真核细胞中Pre-mRNA的剪接。它们的功能在癌症中经常发生变化，为新的治疗方法提供了机会。泛素特异性蛋白水解酶39(USP39)是一个高度保守的去泛素化家族成员，在Pre-mRNA剪接中起着重要的作用，其作用是组装成熟的剪接体复合体。以前的研究已经报道，在各种人类肿瘤类型中，USP39以致癌方式起作用，促进癌症进展并预测不良预后。在此，我们报告了USP39在人食管鳞癌(ESCC)中的差异表达，其表达与包括分化程度和TNM分期在内的临床病理特征显著相关。我们发现USP39在ESCC细胞系中保持上调，在体外和异种移植瘤中发挥促进癌细胞生长的作用。RNA-seq分析表明，shRNA介导的USP39沉默影响了mTOR通路的激活。随后的生化分析表明，USP39通过选择性地促进Rictor mRNA的剪接和成熟来调节mTORC2的活性，尽管不包括其他关键的mTORC成分。总之，我们的报告建议将USP39作为ESCC的生物标志物和致癌因子，并有可能将USP39/mTOR2/Rictor轴作为一种治疗策略。此外，我们的研究将食管癌添加到USP39促进肿瘤发生和发展的癌症名单中。
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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影响因子：
28.2
作者：
Cheng H;Zou Y;Ross JS;Wang K;Liu X;Halmos B;Ali SM;Liu H;Verma A;Montagna C;Chachoua A;Goel S;Schwartz EL;Zhu C;Shan J;Yu Y;Gritsman K;Yelensky R;Lipson D;Otto G;Hawryluk M;Stephens PJ;Miller VA;Piperdi B;Perez-Soler R
通讯作者：
Perez-Soler R
影响因子：
28.2
作者：
Chen J;Crutchley J;Zhang D;Owzar K;Kastan MB
通讯作者：
Kastan MB
影响因子：
14.5
作者：
Lu, Zhaoming;Shi, Xiaojing;Hou, Guiqin
通讯作者：
Hou, Guiqin
影响因子：
--
作者：
Huang Y;Pan XW;Li L;Chen L;Liu X;Lu JL;Zhu XM;Huang H;Yang QW;Ye JQ;Gan SS;Wang LH;Hong Y;Xu DF;Cui XG
通讯作者：
Cui XG
影响因子：
37.3
作者：
Roulin D;Cerantola Y;Dormond-Meuwly A;Demartines N;Dormond O
通讯作者：
Dormond O