ATF3 suppresses metastasis of bladder cancer by regulating gelsolin-mediated remodeling of the actin cytoskeleton
Yuan, Xianglian, Yu, Liang, Li, Junhua, Xie, Guohua, Rong, Tingting, Zhang, Liang, Chen, Jianhua, Meng, Qiaohong, Irving, Aaron T., Wang, Die, Williams, Elizabeth D., Liu, Jun-Ping, Sadler, Anthony J., Williams, Bryan R.G., Shen, Lisong, & Xu, Dakang (2013) ATF3 suppresses metastasis of bladder cancer by regulating gelsolin-mediated remodeling of the actin cytoskeleton. Cancer Research, 73(12), pp. 3625-3637.
Bladder cancer is associated with high recurrence and mortality rates due to metastasis. The elucidation of metastasis suppressors may offer therapeutic opportunities if their mechanisms of action can be elucidated and tractably exploited. In this study, we investigated the clinical and functional significance of the transcription factor activating transcription factor 3 (ATF3) in bladder cancer metastasis. Gene expression analysis revealed that decreased ATF3 was associated with bladder cancer progression and reduced survival of patients with bladder cancer. Correspondingly, ATF3 overexpression in highly metastatic bladder cancer cells decreased migration in vitro and experimental metastasis in vivo. Conversely, ATF3 silencing increased the migration of bladder cancer cells with limited metastatic capability in the absence of any effect on proliferation. In keeping with their increased motility, metastatic bladder cancer cells had increased numbers of actin filaments. Moreover, ATF3 expression correlated with expression of the actin filament severing protein gelsolin (GSN). Mechanistic studies revealed that ATF3 upregulated GSN, whereas ATF3 silencing reduced GSN levels, concomitant with alterations in the actin cytoskeleton. We identified six ATF3 regulatory elements in the first intron of the GSN gene confirmed by chromatin immunoprecipitation analysis. Critically, GSN expression reversed the metastatic capacity of bladder cancer cells with diminished levels of ATF3. Taken together, our results indicate that ATF3 suppresses metastasis of bladder cancer cells, at least in part through the upregulation of GSN-mediated actin remodeling. These findings suggest ATF3 coupled with GSN as prognostic markers for bladder cancer metastasis.
Impact and interest:
Citation counts are sourced monthly from and citation databases.
These databases contain citations from different subsets of available publications and different time periods and thus the citation count from each is usually different. Some works are not in either database and no count is displayed. Scopus includes citations from articles published in 1996 onwards, and Web of Science® generally from 1980 onwards.
Citations counts from theindexing service can be viewed at the linked Google Scholar™ search.
|Item Type:||Journal Article|
|Additional Information:||Articles free to read on journal website after 12 months|
|Keywords:||ATF3, Metastasis, Bladder Cancer, Gelsolin, Actin Cytoskeleton|
|Subjects:||Australian and New Zealand Standard Research Classification > MEDICAL AND HEALTH SCIENCES (110000) > ONCOLOGY AND CARCINOGENESIS (111200)
Australian and New Zealand Standard Research Classification > MEDICAL AND HEALTH SCIENCES (110000) > ONCOLOGY AND CARCINOGENESIS (111200) > Cancer Cell Biology (111201)
|Divisions:||Current > Schools > School of Biomedical Sciences
Current > QUT Faculties and Divisions > Faculty of Health
Current > Institutes > Institute of Health and Biomedical Innovation
|Copyright Owner:||Copyright 2013 American Association for Cancer Research|
|Deposited On:||20 Feb 2014 23:30|
|Last Modified:||28 Jan 2015 00:43|
Repository Staff Only: item control page