Oncotarget

Research Papers:

Ubiquitin C-terminal hydrolase-L1 increases cancer cell invasion by modulating hydrogen peroxide generated via NADPH oxidase 4

Hyun Jung Kim, Venkataraman Magesh, Jae-Jin Lee, Sun Kim, Ulla G. Knaus and Kong-Joo Lee _

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Oncotarget. 2015; 6:16287-16303. https://doi.org/10.18632/oncotarget.3843

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Abstract

Hyun Jung Kim1, Venkataraman Magesh1, Jae-Jin Lee1, Sun Kim1, Ulla G. Knaus2 and Kong-Joo Lee1

1 Graduate School of Pharmaceutical Sciences, College of Pharmacy, Ewha Womans University, Seoul, Korea

2 Conway Institute, University College Dublin, Dublin, Ireland

Correspondence to:

Kong-Joo Lee, email:

Keywords: UCH-L1, ubiquitination, hydrogen peroxide, NOX4, invasion

Received: December 19, 2014 Accepted: March 20, 2015 Published: April 15, 2015

Abstract

This study explored the role of ubiquitin C-terminal hydrolase-L1 (UCH-L1) in the production of ROS and tumor invasion. UCH-L1 was found to increase cellular ROS levels and promote cell invasion. Silencing UCH-L1, as well as inhibition of H2O2 generation by catalase or by DPI, a NOX inhibitor, suppressed the migration potential of B16F10 cells, indicating that UCH-L1 promotes cell migration by up-regulating H2O2 generation. Silencing NOX4, which generates H2O2, with siRNA eliminated the effect of UCH-L1 on cell migration. On the other hand, NOX4 overexpressed in HeLa cells happens to be ubiquitinated, and NOX4 following deubiquitination by UCH-L1, restored H2O2-generating activity. These in vitro findings are consistent with the results obtained in vivo with catalase (-/-) C57BL/6J mice. When H2O2 and UCH-L1 levels were independently varied in these animals, the former by infecting with H2O2-scavenging adenovirus-catalase, and the latter by overexpressing or silencing UCH-L1, pulmonary metastasis of B16F10 cells overexpressing UCH-L1 increased significantly in catalase (-/-) mice. In contrast, invasion did not increase when UCH-L1 was silenced in the B16F10 cells. These findings indicate that H2O2 levels regulated by UCH-L1 are necessary for cell invasion to occur and demonstrate that UCH-L1 promotes cell invasion by up-regulating H2O2 via deubiquitination of NOX4.


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