VOPP1 promotes breast tumorigenesis by interacting with the tumor suppressor WWOX

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.Electronic supplementary materialThe online version of this article (10.1186/s12915-018-0576-6) contains supplementary material, which is available to authorized users.

Comprehensive identification and characterization of somatic copy number alterations in triple‑negative breast cancer

“…VOPP1 overexpression has been observed in several tumor types, such as gastric cancer, head and neck squamous carcinoma and glioma (51)(52)(53). A recent study reported that VOPP1 can promote breast cancer development by interacting with the tumor suppressor WW domain containing oxidoreductase (54). These results suggest that VOPP1 may serve an important role in TNBC carcinogenesis and could be exploited to develop therapies for patients with TNBC.…”

Delineating WWOX Protein Interactome by Tandem Affinity Purification-Mass Spectrometry: Identification of Top Interactors and Key Metabolic Pathways Involved

“…Furthermore, reciprocal co-IP with all of the partners for each interaction was observed (Figure 3A). Very recently, Bonin et al (46) have also identified VOPP1 as a WWOX interactor in human cells by means of yeast-two hybrids and demonstrated that the WW1 region is the interacting domain mostly with the 162 PPPY 165 motif of VOPP1.…”

“…VOPP1 protein structure includes a transmembrane domain and it was reported to partially co-localize with perinuclear lysosomes, suggesting that VOPP1 containing vesicles enter and participate in final lysosomal pathways (54). Very recently, Bonin et al (46). using a yeast-two-hybrid system and co-IP reported that VOPP1 physically interacts with WWOX.…”

<p>LINC01410 Knockdown Suppresses Cervical Cancer Growth and Invasion via Targeting miR-2467-3p/VOPP1 Axis</p>

“…36 Recently, Bonin et al indicated that VOPP1 contributes to breast cancer progression. 37 Its role in CC is largely unknown. In our study, we found that VOPP1 was upregulated in CC tissues.…”