TY  - JOUR
AU  - Avenhaus, Alicia
AU  - Velimirović, Milica
AU  - Bulkescher, Julia
AU  - Scheffner, Martin
AU  - Hoppe-Seyler, Felix
AU  - Hoppe-Seyler, Karin
TI  - E6AP is essential for the proliferation of HPV-positive cancer cells by preventing senescence.
JO  - PLoS pathogens
VL  - 21
IS  - 2
SN  - 1553-7366
CY  - Lawrence, Kan.
PB  - PLoS
M1  - DKFZ-2025-00316
SP  - e1012914 -
PY  - 2025
N1  - #EA:D365#LA:D365#
AB  - 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.
KW  - Humans
KW  - Cellular Senescence: physiology
KW  - Oncogene Proteins, Viral: metabolism
KW  - Oncogene Proteins, Viral: genetics
KW  - Ubiquitin-Protein Ligases: metabolism
KW  - Ubiquitin-Protein Ligases: genetics
KW  - Tumor Suppressor Protein p53: metabolism
KW  - Papillomavirus Infections: virology
KW  - Papillomavirus Infections: metabolism
KW  - Cell Proliferation
KW  - Repressor Proteins: metabolism
KW  - Repressor Proteins: genetics
KW  - Papillomavirus E7 Proteins: metabolism
KW  - Papillomavirus E7 Proteins: genetics
KW  - Cell Line, Tumor
KW  - Oncogene Proteins, Viral (NLM Chemicals)
KW  - Ubiquitin-Protein Ligases (NLM Chemicals)
KW  - UBE3A protein, human (NLM Chemicals)
KW  - Tumor Suppressor Protein p53 (NLM Chemicals)
KW  - Repressor Proteins (NLM Chemicals)
KW  - Papillomavirus E7 Proteins (NLM Chemicals)
KW  - E6 protein, Human papillomavirus type 16 (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:39919145
C2  - pmc:PMC11805377
DO  - DOI:10.1371/journal.ppat.1012914
UR  - https://inrepo02.dkfz.de/record/298616
ER  -