Abstract
BackgroundThe WW domain-containing oxidoreductase (WWOX) gene, frequently altered in breast cancer, encodes a tumor suppressor whose function is mediated through its interactions with cancer-related proteins, such as the pro-apoptotic protein p73α.ResultsTo better understand the involvement of WWOX in breast tumorigenesis, we performed a yeast two-hybrid screen and co-immunoprecipitation assays to identify novel partners of this protein. We characterized the vesicular overexpressed in cancer pro-survival protein 1 (VOPP1) as a new regulator of WWOX. In breast cancer cells, VOPP1 sequestrates WWOX in lysosomes, impairs its ability to associate with p73α, and inhibits WWOX-dependent apoptosis. Overexpressed VOPP1 potentiates cellular transformation and enhances the growth of transplanted tumors in vivo. VOPP1 is overexpressed in breast tumors, especially in tumors that retain WWOX. Moreover, increased expression of VOPP1 is associated with reduced survival of patients with WWOX-positive, but not with WWOX-negative, tumors.ConclusionsThese findings emphasize the importance of the sequestration of WWOX by VOPP1 in addition to WWOX loss in breast tumors and define VOPP1 as a novel oncogene promoting breast carcinogenesis by inhibiting the anti-tumoral effect of WWOX.
Highlights
The WW domain-containing oxidoreductase (WWOX) gene, frequently altered in breast cancer, encodes a tumor suppressor whose function is mediated through its interactions with cancer-related proteins, such as the pro-apoptotic protein p73α
To validate that the vesicular overexpressed in cancer pro-survival protein 1 (VOPP1)-WWOX interaction occurred in mammalian cells, we generated a Flag-tagged VOPP1 expression construct that was co-expressed with a Myc-tagged WWOX plasmid in HEK-293T cells
We found that WWOX co-precipitated with VOPP1 indicating that endogenous WWOX and VOPP1 were physically associated in breast cancer cells
Summary
The WW domain-containing oxidoreductase (WWOX) gene, frequently altered in breast cancer, encodes a tumor suppressor whose function is mediated through its interactions with cancer-related proteins, such as the pro-apoptotic protein p73α. WWOX has been characterized primarily as a tumor suppressor gene spanning the fragile site FRA16D [1]. Homozygous mutations of WWOX were recently identified as responsible for an inherited neural disorder characterized by cerebellar. In human cancers, according to The Cancer Genome Atlas, mutations affecting the WWOX gene are rare events (Reference 3 and http/www.cbioportal.org for updates). Altered WWOX expression is frequent in tumors, which is mainly due to hemi- and homozygous loss and rearrangements on chromosome arm 16q [3, 5].
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