TY  - JOUR
AU  - Ridinger, Johannes
AU  - Koeneke, Emily
AU  - Kolbinger, Fiona
AU  - Koerholz, Katharina
AU  - Mahboobi, Siavosh
AU  - Hellweg, Lars
AU  - Gunkel, Nikolas
AU  - Miller, Aubry
AU  - Peterziel, Heike
AU  - Schmezer, Peter
AU  - Hamacher-Brady, Anne
AU  - Witt, Olaf
AU  - Oehme, Ina
TI  - Dual role of HDAC10 in lysosomal exocytosis and DNA repair promotes neuroblastoma chemoresistance.
JO  - Scientific reports
VL  - 8
IS  - 1
SN  - 2045-2322
CY  - London
PB  - Nature Publishing Group
M1  - DKFZ-2018-01228
SP  - 10039
PY  - 2018
AB  - 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.
LB  - PUB:(DE-HGF)16
C6  - pmid:29968769
C2  - pmc:PMC6030077
DO  - DOI:10.1038/s41598-018-28265-5
UR  - https://inrepo02.dkfz.de/record/136790
ER  -