Ubiquitin-Specific Protease 4-Mediated Deubiquitination and Stabilization of PRL-3 Is Required for Potentiating Colorectal Oncogenesis
PUBLISHED: 2016-02-17  555 total views, 1 today

Cheng Xing1Xing-Xing Lu2Peng-Da Guo2Tong Shen2Shen Zhang2,Xiao-Shun He2Wen-Juan Gan2Xiu-Ming Li2Jing-Ru Wang2Yuan-Yuan Zhao2Hua Wu2,*, and Jian-Ming Li1,2,*


Author Affiliations

1Department of Pathology, Nanfang Hospital, Southern Medical University, Guangzhou, China.

2Pathology Center and Department of Pathology, Soochow University, Suzhou, China.


*Corresponding Authors:
Jian-Ming Li, Department of Pathology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China. Phone: 86-512-65882673; Fax: 86-512-65882673; E-mail:lixinyue@fimmu.com; and Hua Wu, Pathology Center and Department of Pathology, Soochow University, Suzhou 215123, China. Phone: 86-512-65882673; Fax: 86-512-65882673; E-mail: wuhua@suda.edu.cn

Abstract

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 invasion in vitro and metastasis in 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.

Disclaimer: Only abstract of articles from non-members were published. This page aims to promote Chinese scientific research. There is no conflicts of interest with any journals reserved the copyright. For more please contact the author.

Author
Dr. Li Jianming
+ Author Profile

Dr. Li Jianming

Distinguished Professor and Pathology Center Director ofSuzhou University

Email: jianmingli@suda.edu.cn

 

Expertise

Function research of new type tumor metastasis related gene

Epigenetic mechanism of tumor metastasis regulation


Research project

The role and related signal networks of SATB2 in CRC metastasis.

New PRL-3 regulating mechanisms in CRC metastasis.

The correlation study of EMT and CRC stem cells.

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