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@ARTICLE{Bayer:303494,
      author       = {M. Bayer and J. Zajakina and M. Schäfer and K. Salmina and
                      F. Rumnieks and J. Jansons and F. Bestvater$^*$ and R. Kurg
                      and J. Erenpreisa and M. Hausmann},
      title        = {{C}hemotherapy ({E}toposide)-{I}nduced {I}ntermingling of
                      {H}eterochromatin and {E}uchromatin {C}ompartments in
                      {S}enescent {PA}-1 {E}mbryonal {C}arcinoma {C}ells.},
      journal      = {Cancers},
      volume       = {17},
      number       = {15},
      issn         = {2072-6694},
      address      = {Basel},
      publisher    = {MDPI},
      reportid     = {DKFZ-2025-01685},
      pages        = {2480},
      year         = {2025},
      abstract     = {Background: Often, neoadjuvant therapy, which relies on the
                      induction of double-strand breaks (DSBs), is used prior to
                      surgery to shrink tumors by inducing cancer cell apoptosis.
                      However, recent studies have suggested that this treatment
                      may also induce a fluctuating state between senescence and
                      stemness in PA-1 embryonal carcinoma cells, potentially
                      affecting therapeutic outcomes. Thus, the respective
                      epigenetic pathways are up or downregulated over a time
                      period of days. These fluctuations go hand in hand with
                      changes in spatial DNA organization. Methods: By means of
                      Single-Molecule Localization Microscopy in combination with
                      mathematical evaluation tools for pointillist data sets, we
                      investigated the organization of euchromatin and
                      heterochromatin at the nanoscale on the third and fifth day
                      after etoposide treatment. Results: Using fluorescently
                      labeled antibodies against H3K9me3 (heterochromatin
                      tri-methylation sites) and H3K4me3 (euchromatin
                      tri-methylation sites), we found that the induction of DSBs
                      led to the de-condensation of heterochromatin and compaction
                      of euchromatin, with a peak effect on day 3 after the
                      treatment. On day 3, we also observed the co-localization of
                      euchromatin and heterochromatin, which have marks that
                      usually occur in exclusive low-overlapping network-like
                      compartments. The evaluation of the SMLM data using
                      topological tools (persistent homology and persistent
                      imaging) and principal component analysis, as well as the
                      confocal microscopy analysis of H3K9me3- and H3K4me3-stained
                      PA-1 cells, supported the findings that distinct shifts in
                      euchromatin and heterochromatin organization took place in a
                      subpopulation of these cells during the days after the
                      treatment. Furthermore, by means of flow cytometry, it was
                      shown that the rearrangements in chromatin organization
                      coincided with the simultaneous upregulation of the stemness
                      promotors OCT4A and SOX2 and senescence promotors p21Cip1
                      and p27. Conclusions: Our findings suggest potential
                      applications to improve cancer therapy by inhibiting
                      chromatin remodeling and preventing therapy-induced
                      senescence.},
      keywords     = {DNA damage by etoposide (Other) / cell-fate (Other) /
                      chromatin re-organization in tumor cells (Other) /
                      senescence (Other) / single-molecule localization microscopy
                      (Other) / statistical and topological data evaluation
                      (Other) / stemness self-renewal (Other)},
      cin          = {W210},
      ddc          = {610},
      cid          = {I:(DE-He78)W210-20160331},
      pnm          = {319H - Addenda (POF4-319H)},
      pid          = {G:(DE-HGF)POF4-319H},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:40805179},
      doi          = {10.3390/cancers17152480},
      url          = {https://inrepo02.dkfz.de/record/303494},
}