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@ARTICLE{Ridinger:136790,
      author       = {J. Ridinger$^*$ and E. Koeneke$^*$ and F. Kolbinger$^*$ and
                      K. Koerholz$^*$ and S. Mahboobi and L. Hellweg$^*$ and N.
                      Gunkel$^*$ and A. Miller$^*$ and H. Peterziel$^*$ and P.
                      Schmezer$^*$ and A. Hamacher-Brady and O. Witt$^*$ and I.
                      Oehme$^*$},
      title        = {{D}ual role of {HDAC}10 in lysosomal exocytosis and {DNA}
                      repair promotes neuroblastoma chemoresistance.},
      journal      = {Scientific reports},
      volume       = {8},
      number       = {1},
      issn         = {2045-2322},
      address      = {London},
      publisher    = {Nature Publishing Group},
      reportid     = {DKFZ-2018-01228},
      pages        = {10039},
      year         = {2018},
      abstract     = {Drug resistance is a leading cause for treatment failure in
                      many cancers, including neuroblastoma, the most common solid
                      extracranial childhood malignancy. Previous studies from our
                      lab indicate that histone deacetylase 10 (HDAC10) is
                      important for the homeostasis of lysosomes, i.e. acidic
                      vesicular organelles involved in the degradation of various
                      biomolecules. Here, we show that depleting or inhibiting
                      HDAC10 results in accumulation of lysosomes in
                      chemotherapy-resistant neuroblastoma cell lines, as well as
                      in the intracellular accumulation of the weakly basic
                      chemotherapeutic doxorubicin within lysosomes. Interference
                      with HDAC10 does not block doxorubicin efflux from cells via
                      P-glycoprotein inhibition, but rather via inhibition of
                      lysosomal exocytosis. In particular, intracellular
                      doxorubicin does not remain trapped in lysosomes but also
                      accumulates in the nucleus, where it promotes neuroblastoma
                      cell death. Our data suggest that lysosomal exocytosis under
                      doxorubicin treatment is important for cell survival and
                      that inhibition of HDAC10 further induces DNA double-strand
                      breaks (DSBs), providing additional mechanisms that
                      sensitize neuroblastoma cells to doxorubicin. Taken
                      together, we demonstrate that HDAC10 inhibition in
                      combination with doxorubicin kills neuroblastoma, but not
                      non-malignant cells, both by impeding drug efflux and
                      enhancing DNA damage, providing a novel opportunity to
                      target chemotherapy resistance.},
      cin          = {G340 / L101 / G404 / C010},
      ddc          = {000},
      cid          = {I:(DE-He78)G340-20160331 / I:(DE-He78)L101-20160331 /
                      I:(DE-He78)G404-20160331 / I:(DE-He78)C010-20160331},
      pnm          = {317 - Translational cancer research (POF3-317)},
      pid          = {G:(DE-HGF)POF3-317},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:29968769},
      pmc          = {pmc:PMC6030077},
      doi          = {10.1038/s41598-018-28265-5},
      url          = {https://inrepo02.dkfz.de/record/136790},
}