TY  - JOUR
AU  - Velimirovic, Milica
AU  - Avenhaus, Alicia
AU  - Lohrey, Claudia
AU  - Bulkescher, Julia
AU  - Hoppe-Seyler, Felix
AU  - Hoppe-Seyler, Karin
TI  - 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.
JO  - Journal of medical virology
VL  - 97
IS  - 6
SN  - 0146-6615
CY  - Bognor Regis [u.a.]
PB  - Wiley
M1  - DKFZ-2025-01130
SP  - e70422
PY  - 2025
N1  - #EA:D365#LA:D365#
AB  - 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.
KW  - Humans
KW  - Cellular Senescence
KW  - Cell Line, Tumor
KW  - Trans-Activators: genetics
KW  - Trans-Activators: metabolism
KW  - Cell Hypoxia
KW  - Papillomaviridae
KW  - Papillomavirus Infections
KW  - Cell Cycle Proteins
KW  - Proto-Oncogene Proteins c-myb
KW  - A‐MYB (Other)
KW  - B‐MYB (Other)
KW  - cervical cancer (Other)
KW  - human papillomavirus (HPV) (Other)
KW  - hypoxia (Other)
KW  - senescence (Other)
KW  - Trans-Activators (NLM Chemicals)
KW  - MYBL2 protein, human (NLM Chemicals)
KW  - MYB protein, human (NLM Chemicals)
KW  - Cell Cycle Proteins (NLM Chemicals)
KW  - Proto-Oncogene Proteins c-myb (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:40444458
C2  - pmc:PMC12123558
DO  - DOI:10.1002/jmv.70422
UR  - https://inrepo02.dkfz.de/record/301746
ER  -