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

doi:10.1002/ijc.29226

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

Neurology

Research output: Contribution to journal › Article › peer-review

49 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 language	English (US)
Pages (from-to)	1792-1802
Number of pages	11
Journal	International Journal of Cancer
Volume	136
Issue number	8
DOIs	https://doi.org/10.1002/ijc.29226
State	Published - Apr 15 2015

Funding

Keywords

Cell migration
Colorectal cancer
Robo1
Slit2
USP33

ASJC Scopus subject areas

Oncology
Cancer Research

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1002/ijc.29226

Cite this

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title = "USP33 mediates Slit-Robo signaling in inhibiting colorectal cancer cell migration",

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.",

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

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T1 - USP33 mediates Slit-Robo signaling in inhibiting colorectal cancer cell migration

AU - Huang, Zhaohui

AU - Wen, Pushuai

AU - Kong, Ruirui

AU - Cheng, Haipeng

AU - Zhang, Binbin

AU - Quan, Cao

AU - Bian, Zehua

AU - Chen, Mengmeng

AU - Zhang, Zhenfeng

AU - Chen, Xiaoping

AU - Du, Xiang

AU - Liu, Jianghong

AU - Zhu, Li

AU - Fushimi, Kazuo

AU - Hua, Dong

AU - Wu, Jane Y.

PY - 2015/4/15

Y1 - 2015/4/15

N2 - 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.

AB - 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.

KW - Cell migration

KW - Colorectal cancer

KW - Robo1

KW - Slit2

KW - USP33

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

Abstract

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Keywords

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UN SDGs

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