WWOX Loses the Ability to Regulate Oncogenic AP-2γ and Synergizes with Tumor Suppressor AP-2α in High-Grade Bladder Cancer
The cytogenic locus of the <i>WWOX</i> gene overlaps with the second most active fragile site, FRA16D, which is present at a higher frequency in bladder cancer (BLCA) patients with smoking habit, a known risk factor of this tumor. Recently, we demonstrated the relevance of the role of WW...
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MDPI AG
2021-06-01
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| Series: | Cancers |
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| Online Access: | https://www.mdpi.com/2072-6694/13/12/2957 |
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| author | Damian Kołat Żaneta Kałuzińska Andrzej K. Bednarek Elżbieta Płuciennik |
| author_facet | Damian Kołat Żaneta Kałuzińska Andrzej K. Bednarek Elżbieta Płuciennik |
| author_sort | Damian Kołat |
| collection | DOAJ |
| description | The cytogenic locus of the <i>WWOX</i> gene overlaps with the second most active fragile site, FRA16D, which is present at a higher frequency in bladder cancer (BLCA) patients with smoking habit, a known risk factor of this tumor. Recently, we demonstrated the relevance of the role of WWOX in grade 2 BLCA in collaboration with two AP-2 transcription factors whose molecular actions supported or opposed pro-cancerous events, suggesting a distinct character. As further research is needed on higher grades, the aim of the present study was to examine WWOX-AP-2 functionality in grade 3 and 4 BLCA using equivalent in vitro methodology with additional transcriptome profiling of cellular variants. WWOX and AP-2α demonstrated similar anti-cancer functionality in most biological processes with subtle differences in MMP-2/9 regulation; this contradicted that of AP-2γ, whose actions potentiated cancer progression. Simultaneous overexpression of WWOX and AP-2α/AP-2γ revealed that single discrepancies appear in WWOX-AP-2α collaboration but only at the highest BLCA grade; WWOX-AP-2α collaboration was considered anti-cancer. However, WWOX only appeared to have residual activity against oncogenic AP-2γ in grade 3 and 4: variants with either AP-2γ overexpression alone or combined WWOX and AP-2γ overexpression demonstrated similar pro-tumoral behavior. Transcriptome profiling with further gene ontology certified biological processes investigated in vitro and indicated groups of genes consisting of AP-2 targets and molecules worth investigation as biomarkers. In conclusion, tumor suppressor synergism between WWOX and AP-2α is unimpaired in high-grade BLCA compared to intermediate grade, yet the ability of WWOX to guide oncogenic AP-2γ is almost completely lost. |
| first_indexed | 2024-03-10T10:27:10Z |
| format | Article |
| id | doaj.art-40afa859e2e6435fbf96aaba23cf1488 |
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| issn | 2072-6694 |
| language | English |
| last_indexed | 2024-03-10T10:27:10Z |
| publishDate | 2021-06-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cancers |
| spelling | doaj.art-40afa859e2e6435fbf96aaba23cf14882023-11-21T23:55:14ZengMDPI AGCancers2072-66942021-06-011312295710.3390/cancers13122957WWOX Loses the Ability to Regulate Oncogenic AP-2γ and Synergizes with Tumor Suppressor AP-2α in High-Grade Bladder CancerDamian Kołat0Żaneta Kałuzińska1Andrzej K. Bednarek2Elżbieta Płuciennik3Department of Molecular Carcinogenesis, Medical University of Lodz, 90-752 Lodz, PolandDepartment of Molecular Carcinogenesis, Medical University of Lodz, 90-752 Lodz, PolandDepartment of Molecular Carcinogenesis, Medical University of Lodz, 90-752 Lodz, PolandDepartment of Molecular Carcinogenesis, Medical University of Lodz, 90-752 Lodz, PolandThe cytogenic locus of the <i>WWOX</i> gene overlaps with the second most active fragile site, FRA16D, which is present at a higher frequency in bladder cancer (BLCA) patients with smoking habit, a known risk factor of this tumor. Recently, we demonstrated the relevance of the role of WWOX in grade 2 BLCA in collaboration with two AP-2 transcription factors whose molecular actions supported or opposed pro-cancerous events, suggesting a distinct character. As further research is needed on higher grades, the aim of the present study was to examine WWOX-AP-2 functionality in grade 3 and 4 BLCA using equivalent in vitro methodology with additional transcriptome profiling of cellular variants. WWOX and AP-2α demonstrated similar anti-cancer functionality in most biological processes with subtle differences in MMP-2/9 regulation; this contradicted that of AP-2γ, whose actions potentiated cancer progression. Simultaneous overexpression of WWOX and AP-2α/AP-2γ revealed that single discrepancies appear in WWOX-AP-2α collaboration but only at the highest BLCA grade; WWOX-AP-2α collaboration was considered anti-cancer. However, WWOX only appeared to have residual activity against oncogenic AP-2γ in grade 3 and 4: variants with either AP-2γ overexpression alone or combined WWOX and AP-2γ overexpression demonstrated similar pro-tumoral behavior. Transcriptome profiling with further gene ontology certified biological processes investigated in vitro and indicated groups of genes consisting of AP-2 targets and molecules worth investigation as biomarkers. In conclusion, tumor suppressor synergism between WWOX and AP-2α is unimpaired in high-grade BLCA compared to intermediate grade, yet the ability of WWOX to guide oncogenic AP-2γ is almost completely lost.https://www.mdpi.com/2072-6694/13/12/2957<i>WWOX</i><i>TFAP2A</i><i>TFAP2C</i>AP-2alphaAP-2gammaAP-2 transcription factors |
| spellingShingle | Damian Kołat Żaneta Kałuzińska Andrzej K. Bednarek Elżbieta Płuciennik WWOX Loses the Ability to Regulate Oncogenic AP-2γ and Synergizes with Tumor Suppressor AP-2α in High-Grade Bladder Cancer Cancers <i>WWOX</i> <i>TFAP2A</i> <i>TFAP2C</i> AP-2alpha AP-2gamma AP-2 transcription factors |
| title | WWOX Loses the Ability to Regulate Oncogenic AP-2γ and Synergizes with Tumor Suppressor AP-2α in High-Grade Bladder Cancer |
| title_full | WWOX Loses the Ability to Regulate Oncogenic AP-2γ and Synergizes with Tumor Suppressor AP-2α in High-Grade Bladder Cancer |
| title_fullStr | WWOX Loses the Ability to Regulate Oncogenic AP-2γ and Synergizes with Tumor Suppressor AP-2α in High-Grade Bladder Cancer |
| title_full_unstemmed | WWOX Loses the Ability to Regulate Oncogenic AP-2γ and Synergizes with Tumor Suppressor AP-2α in High-Grade Bladder Cancer |
| title_short | WWOX Loses the Ability to Regulate Oncogenic AP-2γ and Synergizes with Tumor Suppressor AP-2α in High-Grade Bladder Cancer |
| title_sort | wwox loses the ability to regulate oncogenic ap 2γ and synergizes with tumor suppressor ap 2α in high grade bladder cancer |
| topic | <i>WWOX</i> <i>TFAP2A</i> <i>TFAP2C</i> AP-2alpha AP-2gamma AP-2 transcription factors |
| url | https://www.mdpi.com/2072-6694/13/12/2957 |
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