%0 Journal Article
%A Velimirovic, Milica
%A Avenhaus, Alicia
%A Lohrey, Claudia
%A Bulkescher, Julia
%A Hoppe-Seyler, Felix
%A Hoppe-Seyler, Karin
%T Hypoxic HPV-Positive Cancer Cells Are Particularly Sensitive to the Pro-Senescent Effects of B-MYB Repression Due to the Lack of Compensatory A-MYB Induction.
%J Journal of medical virology
%V 97
%N 6
%@ 0146-6615
%C Bognor Regis [u.a.]
%I Wiley
%M DKFZ-2025-01130
%P e70422
%D 2025
%Z #EA:D365#LA:D365#
%X Tumor hypoxia is typically linked to increased therapy resistance and poor prognosis of many malignancies, including HPV-positive cancers. One possible resistance mechanism is the increased resistance of hypoxic tumor cells to cellular senescence. It is thus highly interesting to identify strategies which could increase their pro-senescent susceptibility. In comparative analyses of normoxic and hypoxic HPV-positive cancer cells, we here uncover that the interconnection between B-MYB and its paralog A-MYB plays a key role for their senescence response, but shows a differential regulation under normoxia and hypoxia. In specific, we demonstrate that the pro-senescent response to B-MYB loss is counteracted by a compensatory upregulation of A-MYB under normoxia. Therefore, efficient induction of senescence in normoxic cells requires the downregulation of both B-MYB and A-MYB. Interestingly, this compensatory A-MYB induction is absent under hypoxia, rendering hypoxic cancer cells particularly sensitive to the pro-senescent effect of B-MYB repression. We further show that these regulatory effects are not confined to HPV-positive cancer cells, indicating that they could be broadly conserved between different cancer types. Collectively, our findings reveal that hypoxic cancer cells are particularly sensitive to B-MYB inhibition, which could provide a new strategy to target this therapeutically challenging cancer cell population.
%K Humans
%K Cellular Senescence
%K Cell Line, Tumor
%K Trans-Activators: genetics
%K Trans-Activators: metabolism
%K Cell Hypoxia
%K Papillomaviridae
%K Papillomavirus Infections
%K Cell Cycle Proteins
%K Proto-Oncogene Proteins c-myb
%K A‐MYB (Other)
%K B‐MYB (Other)
%K cervical cancer (Other)
%K human papillomavirus (HPV) (Other)
%K hypoxia (Other)
%K senescence (Other)
%K Trans-Activators (NLM Chemicals)
%K MYBL2 protein, human (NLM Chemicals)
%K MYB protein, human (NLM Chemicals)
%K Cell Cycle Proteins (NLM Chemicals)
%K Proto-Oncogene Proteins c-myb (NLM Chemicals)
%F PUB:(DE-HGF)16
%9 Journal Article
%$ pmid:40444458
%2 pmc:PMC12123558
%R 10.1002/jmv.70422
%U https://inrepo02.dkfz.de/record/301746