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USP 33 mediates S lit‐ R obo signaling in inhibiting colorectal cancer cell migration
Author(s) -
Huang Zhaohui,
Wen Pushuai,
Kong Ruirui,
Cheng Haipeng,
Zhang Binbin,
Quan Cao,
Bian Zehua,
Chen Mengmeng,
Zhang Zhenfeng,
Chen Xiaoping,
Du Xiang,
Liu Jianghong,
Zhu Li,
Fushimi Kazuo,
Hua Dong,
Wu Jane Y.
Publication year - 2014
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.29226
Subject(s) - colorectal cancer , cancer research , cell migration , downregulation and upregulation , metastasis , biology , deubiquitinating enzyme , cell growth , cancer , cell , ubiquitin , gene , genetics
Originally discovered in neuronal guidance, the Slit‐Robo pathway is emerging as an important player in human cancers. However, its involvement and mechanism in colorectal cancer (CRC) remains to be elucidated. Here, we report that Slit2 expression is reduced in CRC tissues compared with adjacent noncancerous tissues. Extensive promoter hypermethylation of the Slit2 gene has been observed in CRC cells, which provides a mechanistic explanation for the Slit2 downregulation in CRC. Functional studies showed that Slit2 inhibits CRC cell migration in a Robo‐dependent manner. Robo‐interacting ubiquitin‐specific protease 33 (USP33) is required for the inhibitory function of Slit2 on CRC cell migration by deubiquitinating and stabilizing Robo1. USP33 expression is downregulated in CRC samples, and reduced USP33 mRNA levels are correlated with increased tumor grade, lymph node metastasis and poor patient survival. Taken together, our data reveal USP33 as a previously unknown tumor‐suppressing gene for CRC by mediating the inhibitory function of Slit‐Robo signaling on CRC cell migration. Our work suggests the potential value of USP33 as an independent prognostic marker of CRC.