Ubiquitin-Specific Protease 4-Mediated Deubiquitination and Stabilization of PRL-3 Is Required for Potentiating Colorectal Oncogenesis
Ubiquitin-Specific Protease 4-Mediated Deubiquitination and Stabilization of PRL-3 Is Required for Potentiating Colorectal Oncogenesis
复制标题
泛素特异性蛋白酶 4 介导的去泛素化和 PRL-3 的稳定是增强结直肠肿瘤发生所必需的
DOI：
10.1158/0008-5472.can-14-3595
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发表时间：
2016-01-01
期刊：
影响因子：
11.2
通讯作者：
Li, Jian-Ming
中科院分区：
文献类型：
--
作者：
Xing, Cheng;Lu, Xing-Xing;Li, Jian-Ming
泛素特异性蛋白酶4（Ubiquitin specific protease 4，USP 4）是一种去泛素化酶，在调节p53和TGFβ信号通路中起关键作用，提示其在肿瘤发生中的重要性。然而，USP 4在癌症（包括结直肠癌）中的机制和调节作用在很大程度上仍然难以捉摸。在这里，我们提出了USP 4调节结直肠癌生长、侵袭和转移的第一个证据。USP 4在结直肠癌组织中的表达显著升高，并且与肿瘤大小、分化、远处转移和较差的生存率显著相关。USP 4的敲除减少了结肠直肠癌细胞的生长、集落形成、迁移和体外侵袭以及体内转移。重要的是，我们发现再生肝磷酸酶-3（PRL-3）对于结直肠癌中USP 4介导的致癌活性是必不可少的。在机制上，我们观察到USP 4通过去泛素化与PRL-3相互作用并稳定PRL-3。这导致Akt的激活和E-钙粘蛋白的减少，这是癌细胞生长和转移的关键调节因子。临床样本的检查证实USP 4表达与PRL-3蛋白表达呈正相关，但与mRNA转录水平无关。总之，我们的研究结果表明，USP 4的异常表达有助于结直肠癌的发展和进展，并揭示了USP 4介导的致癌活性的关键机制。这些观察结果表明，利用蛋白水解降解过程进行治疗操作的潜力可能为改善结肠直肠癌治疗策略提供急需的新方法（Cancer Res; 76（1）; 83-95）。©2015 AACR.
Ubiquitin specific protease 4 (USP4) is a deubiquitinating enzyme with key roles in the regulation of p53 and TGFβ signaling, suggesting its importance in tumorigenesis. However, the mechanisms and regulatory roles of USP4 in cancer, including colorectal cancer, remain largely elusive. Here, we present the first evidence that USP4 regulates the growth, invasion, and metastasis of colorectal cancer. USP4 expression was significantly elevated in colorectal cancer tissues and was significantly associated with tumor size, differentiation, distant metastasis, and poor survival. Knockdown of USP4 diminished colorectal cancer cell growth, colony formation, migration, and invasionin vitroand metastasisin vivo. Importantly, we found that phosphatase of regenerating liver-3 (PRL-3) is indispensable for USP4-mediated oncogenic activity in colorectal cancer. Mechanistically, we observed that USP4 interacted with and stabilized PRL-3 via deubiquitination. This resulted in activation of Akt and reduction of E-cadherin, critical regulators of cancer cell growth and metastasis. Examination of clinical samples confirmed that USP4 expression positively correlates with PRL-3 protein expression, but not mRNA transcript levels. Taken together, our results demonstrate that aberrant expression of USP4 contributes to the development and progression of colorectal cancer and reveal a critical mechanism underlying USP4-mediated oncogenic activity. These observations suggest that the potential of harnessing proteolytic degradation processes for therapeutic manipulation may offer a much-needed new approach for improving colorectal cancer treatment strategies.Cancer Res; 76(1); 83–95. ©2015 AACR.