eprintid: 37467
rev_number: 13
eprint_status: archive
userid: 9330
dir: disk0/00/03/74/67
datestamp: 2025-10-27 14:15:32
lastmod: 2025-10-29 18:03:10
status_changed: 2025-10-27 14:15:32
type: doctoralThesis
metadata_visibility: show
creators_name: Velimirovic, Milica
title: Senescence Control in Normoxic and Hypoxic
HPV-Positive Cancer Cells:
The Interplay between B-MYB and A-MYB
subjects: ddc-570
divisions: i-140001
adv_faculty: af-14
cterms_swd: HPV
cterms_swd: Hypoxia
cterms_swd: Senescence
abstract: Hypoxia is a hallmark of solid tumors, including HPV-positive cervical cancers, and it poses a
significant challenge to cancer treatment, as hypoxic tumor regions are often associated with
increased therapy resistance and poor patient prognosis. One possible contributing factor to
this resistance is the ability of hypoxic cancer cells to evade cellular senescence – a process
leading to an irreversible growth arrest. While the repression of the HPV E6/E7 oncogenes in
normoxic HPV-positive cells efficiently induces senescence, hypoxic HPV-positive cells,
despite efficiently shutting off E6/E7 expression, evade senescence and induce a reversible
growth arrest that can be overcome by reoxygenation.
The overall aim of this thesis was to uncover mechanisms that enable hypoxic HPV-positive
cancer cells to evade senescence. Through comparative gene and protein expression
analyses following E6/E7 repression under normoxic and hypoxic conditions, I identified
distinct regulatory patterns of key cell cycle regulatory factors. Notably, B-MYB emerged as a
critical factor differentially regulated under these conditions. Its strong downregulation in
normoxic cells following E6/E7 knockdown was associated with the onset of senescence, while
its sustained expression under hypoxia correlated with senescence evasion, suggesting a role
for B-MYB in controlling this process. To further investigate the functional role of B-MYB, I
performed knockdown experiments and assessed the phenotypic consequences using various
cellular assays. Interestingly, B-MYB depletion led to a partial senescence induction under
normoxia. I further showed that this limited senescence response was due to the compensatory
induction of a B-MYB paralog, A-MYB, which could counteract the pro-senescent effects of
B-MYB loss. Consequently, the combined repression of both B-MYB and A-MYB was needed
for efficient senescence induction under normoxia. Strikingly, I found that this compensatory
mechanism is disrupted under hypoxia, rendering hypoxic cancer cells particularly susceptible
to the pro-senescent effects of B-MYB loss. This increased vulnerability of hypoxic cells could
be reversed by ectopic A-MYB overexpression. Further, my studies revealed that the
B-MYB/A-MYB axis also plays a key role for the senescence response of normoxic and hypoxic
HPV-negative cancer cells of various histological backgrounds, indicating that this newly
discovered mechanism could be broadly conserved across different tumor types.
Collectively, my findings provide novel insights into the regulation of senescence in normoxic
and hypoxic cancer cells and identify B-MYB and A-MYB as central factors in these processes.
Further, they reveal a particular vulnerability of hypoxic cancer cells to B-MYB inhibition that
could be exploited to develop new strategies to target this therapeutically challenging tumor
cell population.
date: 2025
id_scheme: DOI
id_number: 10.11588/heidok.00037467
ppn_swb: 1939711797
own_urn: urn:nbn:de:bsz:16-heidok-374677
date_accepted: 2025-10-10
advisor: HASH(0x55b51307a8a0)
language: eng
bibsort: VELIMIROVISENESCENCE202510
full_text_status: public
place_of_pub: Heidelberg
citation:   Velimirovic, Milica  (2025) Senescence Control in Normoxic and Hypoxic HPV-Positive Cancer Cells: The Interplay between B-MYB and A-MYB.  [Dissertation]     
document_url: https://archiv.ub.uni-heidelberg.de/volltextserver/37467/1/Thesis%20Milica%20Velimirovic.pdf