E6AP is essential for the proliferation of HPV-positive cancer cells by preventing senescence.
Oncogenic types of human papillomaviruses (HPVs) are major human carcinogens. The formation of a trimeric complex between the HPV E6 oncoprotein, the cellular ubiquitin ligase E6AP and the p53 tumor suppressor protein leads to proteolytic p53 degradation and plays a central role for HPV-induced cell...
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| Format: | Article |
| Language: | English |
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Public Library of Science (PLoS)
2025-02-01
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| Series: | PLoS Pathogens |
| Online Access: | https://doi.org/10.1371/journal.ppat.1012914 |
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| author | Alicia Avenhaus Milica Velimirović Julia Bulkescher Martin Scheffner Felix Hoppe-Seyler Karin Hoppe-Seyler |
| author_facet | Alicia Avenhaus Milica Velimirović Julia Bulkescher Martin Scheffner Felix Hoppe-Seyler Karin Hoppe-Seyler |
| author_sort | Alicia Avenhaus |
| collection | DOAJ |
| description | Oncogenic types of human papillomaviruses (HPVs) are major human carcinogens. The formation of a trimeric complex between the HPV E6 oncoprotein, the cellular ubiquitin ligase E6AP and the p53 tumor suppressor protein leads to proteolytic p53 degradation and plays a central role for HPV-induced cell transformation. We here uncover that E6AP silencing in HPV-positive cancer cells ultimately leads to efficient induction of cellular senescence, revealing that E6AP acts as a potent anti-senescent factor in these cells. Thus, although the downregulation of either E6 or E6AP expression also acts partially pro-apoptotic, HPV-positive cancer cells surviving E6 repression proliferate further, whereas they become irreversibly growth-arrested upon E6AP repression. We moreover show that the senescence induction following E6AP downregulation is mechanistically highly dependent on induction of the p53/p21 axis, other than the known pro-senescent response of HPV-positive cancer cells following combined downregulation of the viral E6 and E7 oncoproteins. Of further note, repression of E6AP allows senescence induction in the presence of the anti-senescent HPV E7 protein. Yet, despite these mechanistic differences, the pathways underlying the pro-senescent effects of E6AP or E6/E7 repression ultimately converge by being both dependent on the cellular pocket proteins pRb and p130. Taken together, our results uncover a hitherto unrecognized and potent anti-senescent function of the E6AP protein in HPV-positive cancer cells, which is essential for their sustained proliferation. Our results further indicate that interfering with E6AP expression or function could result in therapeutically desired effects in HPV-positive cancer cells by efficiently inducing an irreversible growth arrest. Since the critical role of the E6/E6AP/p53 complex for viral transformation is conserved between different oncogenic HPV types, this approach could provide a therapeutic strategy, which is not HPV type-specific. |
| format | Article |
| id | doaj-art-0ac5603c29a549678cc77cd538f678eb |
| institution | Kabale University |
| issn | 1553-7366 1553-7374 |
| language | English |
| publishDate | 2025-02-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS Pathogens |
| spelling | doaj-art-0ac5603c29a549678cc77cd538f678eb2025-02-12T05:30:42ZengPublic Library of Science (PLoS)PLoS Pathogens1553-73661553-73742025-02-01212e101291410.1371/journal.ppat.1012914E6AP is essential for the proliferation of HPV-positive cancer cells by preventing senescence.Alicia AvenhausMilica VelimirovićJulia BulkescherMartin ScheffnerFelix Hoppe-SeylerKarin Hoppe-SeylerOncogenic types of human papillomaviruses (HPVs) are major human carcinogens. The formation of a trimeric complex between the HPV E6 oncoprotein, the cellular ubiquitin ligase E6AP and the p53 tumor suppressor protein leads to proteolytic p53 degradation and plays a central role for HPV-induced cell transformation. We here uncover that E6AP silencing in HPV-positive cancer cells ultimately leads to efficient induction of cellular senescence, revealing that E6AP acts as a potent anti-senescent factor in these cells. Thus, although the downregulation of either E6 or E6AP expression also acts partially pro-apoptotic, HPV-positive cancer cells surviving E6 repression proliferate further, whereas they become irreversibly growth-arrested upon E6AP repression. We moreover show that the senescence induction following E6AP downregulation is mechanistically highly dependent on induction of the p53/p21 axis, other than the known pro-senescent response of HPV-positive cancer cells following combined downregulation of the viral E6 and E7 oncoproteins. Of further note, repression of E6AP allows senescence induction in the presence of the anti-senescent HPV E7 protein. Yet, despite these mechanistic differences, the pathways underlying the pro-senescent effects of E6AP or E6/E7 repression ultimately converge by being both dependent on the cellular pocket proteins pRb and p130. Taken together, our results uncover a hitherto unrecognized and potent anti-senescent function of the E6AP protein in HPV-positive cancer cells, which is essential for their sustained proliferation. Our results further indicate that interfering with E6AP expression or function could result in therapeutically desired effects in HPV-positive cancer cells by efficiently inducing an irreversible growth arrest. Since the critical role of the E6/E6AP/p53 complex for viral transformation is conserved between different oncogenic HPV types, this approach could provide a therapeutic strategy, which is not HPV type-specific.https://doi.org/10.1371/journal.ppat.1012914 |
| spellingShingle | Alicia Avenhaus Milica Velimirović Julia Bulkescher Martin Scheffner Felix Hoppe-Seyler Karin Hoppe-Seyler E6AP is essential for the proliferation of HPV-positive cancer cells by preventing senescence. PLoS Pathogens |
| title | E6AP is essential for the proliferation of HPV-positive cancer cells by preventing senescence. |
| title_full | E6AP is essential for the proliferation of HPV-positive cancer cells by preventing senescence. |
| title_fullStr | E6AP is essential for the proliferation of HPV-positive cancer cells by preventing senescence. |
| title_full_unstemmed | E6AP is essential for the proliferation of HPV-positive cancer cells by preventing senescence. |
| title_short | E6AP is essential for the proliferation of HPV-positive cancer cells by preventing senescence. |
| title_sort | e6ap is essential for the proliferation of hpv positive cancer cells by preventing senescence |
| url | https://doi.org/10.1371/journal.ppat.1012914 |
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