%0 Journal Article
%A Avenhaus, Alicia
%A Velimirović, Milica
%A Bulkescher, Julia
%A Scheffner, Martin
%A Hoppe-Seyler, Felix
%A Hoppe-Seyler, Karin
%T E6AP is essential for the proliferation of HPV-positive cancer cells by preventing senescence.
%J PLoS pathogens
%V 21
%N 2
%@ 1553-7366
%C Lawrence, Kan.
%I PLoS
%M DKFZ-2025-00316
%P e1012914 -
%D 2025
%Z #EA:D365#LA:D365#
%X 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.
%K Humans
%K Cellular Senescence: physiology
%K Oncogene Proteins, Viral: metabolism
%K Oncogene Proteins, Viral: genetics
%K Ubiquitin-Protein Ligases: metabolism
%K Ubiquitin-Protein Ligases: genetics
%K Tumor Suppressor Protein p53: metabolism
%K Papillomavirus Infections: virology
%K Papillomavirus Infections: metabolism
%K Cell Proliferation
%K Repressor Proteins: metabolism
%K Repressor Proteins: genetics
%K Papillomavirus E7 Proteins: metabolism
%K Papillomavirus E7 Proteins: genetics
%K Cell Line, Tumor
%K Oncogene Proteins, Viral (NLM Chemicals)
%K Ubiquitin-Protein Ligases (NLM Chemicals)
%K UBE3A protein, human (NLM Chemicals)
%K Tumor Suppressor Protein p53 (NLM Chemicals)
%K Repressor Proteins (NLM Chemicals)
%K Papillomavirus E7 Proteins (NLM Chemicals)
%K E6 protein, Human papillomavirus type 16 (NLM Chemicals)
%F PUB:(DE-HGF)16
%9 Journal Article
%$ pmid:39919145
%2 pmc:PMC11805377
%R 10.1371/journal.ppat.1012914
%U https://inrepo02.dkfz.de/record/298616