title: Ubiquitin-Specific Protease 4-Mediated Deubiquitination and Stabilization of PRL-3 Is Required for Potentiating Colorectal Oncogenesis.
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.
authors.affiliation: Department of Pathology, Nanfang Hospital, Southern Medical University, Guangzhou, China.
authors.forename: Cheng
authors.initials: C
authors.lastname: Xing
authors.affiliation: Pathology Center and Department of Pathology, Soochow University, Suzhou, China.
authors.forename: Xing-Xing
authors.initials: XX
authors.lastname: Lu
authors.affiliation: Pathology Center and Department of Pathology, Soochow University, Suzhou, China.
authors.forename: Peng-Da
authors.initials: PD
authors.lastname: Guo
authors.affiliation: Pathology Center and Department of Pathology, Soochow University, Suzhou, China.
authors.forename: Tong
authors.initials: T
authors.lastname: Shen
authors.affiliation: Pathology Center and Department of Pathology, Soochow University, Suzhou, China.
authors.forename: Shen
authors.initials: S
authors.lastname: Zhang
authors.affiliation: Pathology Center and Department of Pathology, Soochow University, Suzhou, China.
authors.forename: Xiao-Shun
authors.initials: XS
authors.lastname: He
authors.affiliation: Pathology Center and Department of Pathology, Soochow University, Suzhou, China.
authors.forename: Wen-Juan
authors.initials: WJ
authors.lastname: Gan
authors.affiliation: Pathology Center and Department of Pathology, Soochow University, Suzhou, China.
authors.forename: Xiu-Ming
authors.initials: XM
authors.lastname: Li
authors.affiliation: Pathology Center and Department of Pathology, Soochow University, Suzhou, China.
authors.forename: Jing-Ru
authors.initials: JR
authors.lastname: Wang
authors.affiliation: Pathology Center and Department of Pathology, Soochow University, Suzhou, China.
authors.forename: Yuan-Yuan
authors.initials: YY
authors.lastname: Zhao
authors.affiliation: Pathology Center and Department of Pathology, Soochow University, Suzhou, China. lixinyue@fimmu.com wuhua@suda.edu.cn.
authors.forename: Hua
authors.initials: H
authors.lastname: Wu
authors.affiliation: Department of Pathology, Nanfang Hospital, Southern Medical University, Guangzhou, China. Pathology Center and Department of Pathology, Soochow University, Suzhou, China. lixinyue@fimmu.com wuhua@suda.edu.cn.
authors.forename: Jian-Ming
authors.initials: JM
authors.lastname: Li
mesh_terms: D000818:Animals; D018938:Caco-2 Cells; D063646:Carcinogenesis; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic; D015179:Colorectal Neoplasms / Q000201:enzymology / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D004195:Disease Models, Animal; D045325:HCT116 Cells; D057809:HEK293 Cells; D064593:Heterografts; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D009363:Neoplasm Proteins / Q000378:metabolism*; D017027:Protein Tyrosine Phosphatases / Q000378:metabolism*; D015398:Signal Transduction; D043222:Ubiquitin Thiolesterase / Q000378:metabolism*; D064570:Ubiquitin-Specific Proteases; D054875:Ubiquitination
chemical_list: D009363:Neoplasm Proteins; C486203:USP4 protein, human; C484730:PTP4A3 protein, human; D017027:Protein Tyrosine Phosphatases; D043222:Ubiquitin Thiolesterase; D064570:Ubiquitin-Specific Proteases