USP33 mediates Slit-Robo signaling in inhibiting colorectal cancer cell migration

Zhaohui Huang*, Pushuai Wen, Ruirui Kong, Haipeng Cheng, Binbin Zhang, Cao Quan, Zehua Bian, Mengmeng Chen, Zhenfeng Zhang, Xiaoping Chen, Xiang Du, Jianghong Liu, Li Zhu, Kazuo Fushimi, Dong Hua, Jane Y. Wu

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

35 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1792-1802
Number of pages11
JournalInternational Journal of Cancer
Volume136
Issue number8
DOIs
StatePublished - Apr 15 2015

Keywords

  • Cell migration
  • Colorectal cancer
  • Robo1
  • Slit2
  • USP33

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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