Home > Publications database > E6AP is essential for the proliferation of HPV-positive cancer cells by preventing senescence. > print

001     298616
005     20250511020420.0
024 7 _ |a 10.1371/journal.ppat.1012914
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100 1 _ |a Avenhaus, Alicia
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245 _ _ |a E6AP is essential for the proliferation of HPV-positive cancer cells by preventing senescence.
260 _ _ |a Lawrence, Kan.
|c 2025
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520 _ _ |a 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.
536 _ _ |a 314 - Immunologie und Krebs (POF4-314)
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650 _ 7 |a Oncogene Proteins, Viral
|2 NLM Chemicals
650 _ 7 |a Ubiquitin-Protein Ligases
|0 EC 2.3.2.27
|2 NLM Chemicals
650 _ 7 |a UBE3A protein, human
|0 EC 2.3.2.26
|2 NLM Chemicals
650 _ 7 |a Tumor Suppressor Protein p53
|2 NLM Chemicals
650 _ 7 |a Repressor Proteins
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650 _ 7 |a Papillomavirus E7 Proteins
|2 NLM Chemicals
650 _ 7 |a E6 protein, Human papillomavirus type 16
|2 NLM Chemicals
650 _ 2 |a Humans
|2 MeSH
650 _ 2 |a Cellular Senescence: physiology
|2 MeSH
650 _ 2 |a Oncogene Proteins, Viral: metabolism
|2 MeSH
650 _ 2 |a Oncogene Proteins, Viral: genetics
|2 MeSH
650 _ 2 |a Ubiquitin-Protein Ligases: metabolism
|2 MeSH
650 _ 2 |a Ubiquitin-Protein Ligases: genetics
|2 MeSH
650 _ 2 |a Tumor Suppressor Protein p53: metabolism
|2 MeSH
650 _ 2 |a Papillomavirus Infections: virology
|2 MeSH
650 _ 2 |a Papillomavirus Infections: metabolism
|2 MeSH
650 _ 2 |a Cell Proliferation
|2 MeSH
650 _ 2 |a Repressor Proteins: metabolism
|2 MeSH
650 _ 2 |a Repressor Proteins: genetics
|2 MeSH
650 _ 2 |a Papillomavirus E7 Proteins: metabolism
|2 MeSH
650 _ 2 |a Papillomavirus E7 Proteins: genetics
|2 MeSH
650 _ 2 |a Cell Line, Tumor
|2 MeSH
700 1 _ |a Velimirović, Milica
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700 1 _ |a Bulkescher, Julia
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700 1 _ |a Scheffner, Martin
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700 1 _ |a Hoppe-Seyler, Felix
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700 1 _ |a Hoppe-Seyler, Karin
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773 _ _ |a 10.1371/journal.ppat.1012914
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