Human UTP14a promotes colorectal cancer progression by forming a positive regulation loop with c-Myc
Human UTP14a promotes colorectal cancer progression by forming a positive regulation loop with c-Myc
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人 UTP14a 通过与 c-Myc 形成正向调节环促进结直肠癌进展
DOI：
10.1016/j.canlet.2018.10.010
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发表时间：
2019-01-01
期刊：
影响因子：
9.7
通讯作者：
Xing, Baocai
中科院分区：
文献类型：
--
作者：
Zhang, Jingyi;Ren, Pengwei;Xing, Baocai
核仁蛋白hUTP14a是18S rRNA加工所必需的，并促进p53降解。在此，我们报道在结直肠癌（CRC）进展中hUTP14a可稳定c - Myc。首先，核仁hUTP14a在人CRC组织中表达上调。质谱分析在hUTP14a特异性复合物中鉴定出c - Myc及其去泛素化酶泛素特异性蛋白酶36（USP36）。重要的是，hUTP14a与c - Myc相互作用，并以USP36依赖的方式保护c - Myc免受泛素化和降解。我们进一步证明hUTP14a与USP36/Fbw7γ形成复合物以抑制Fbw7γ介导的c - Myc降解。Flag - hUTP14a的异位表达使核仁中的c - Myc富集，表明hUTP14a在核仁中稳定c - Myc。有趣的是，c - Myc激活hUTP14a的转录。通过短发夹RNA敲低hUTP14a可抑制小鼠异种移植物中的肿瘤生长并降低c - Myc水平。值得注意的是，核仁hUTP14a和c - Myc在人CRC组织中共同上调，这种共同上调预示着CRC患者预后不良。因此，破坏hUTP14a - c - Myc的调控可能为一部分CRC患者提供一种潜在的治疗策略。
Nucleolar protein hUTP14a is required for 18S rRNA processing and promotes p53 degradation. Here, we report that hUTP14a stabilizes c-Myc in colorectal cancer (CRC) progression. Firstly, nucleolar hUTP14a is upregulated in human CRC tissues. Mass spectrometry analysis identified c-Myc and its deubiquitinase ubiquitin-specific protease 36 (USP36) in the hUTP14a-specific complex. Importantly, hUTP14a interacts with c-Myc and protects c-Myc from ubiquitination and degradation in a USP36-dependent way. We further demonstrate that hUTP14a forms a complex with USP36/Fbw7 gamma to inhibit Fbw7 gamma-mediated c-Myc degradation. Ectopic expression of Flagh-UTP14a enriches c-Myc in the nucleolus, indicating hUTP14a stabilizes c-Myc in the nucleolus. Interestingly, c-Myc activates transcription of hUTP14a. Knockdown of hUTP14a by short hairpin RNA inhibits tumor growth and decreases c-Myc levels in mouse xenografts. Significantly, nucleolar hUTP14a and c-Myc are co-upregulated in human CRC tissues, and this co-upregulation indicates poor prognosis of CRC patients. Thus, disruption of hUTP14a-c-Myc regulation may provide a potential therapeutic strategy for a subset of CRC patients.