Dual role of HDAC10 in lysosomal exocytosis and DNA repair promotes neuroblastoma chemoresistance

Johannes Ridinger, Emily Koeneke, Fiona R. Kolbinger, Katharina Koerholz, Siavosh Mahboobi, Lars Hellweg, Nikolas Gunkel, Aubry K. Miller, Heike Peterziel, Peter Schmezer, Anne Hamacher-Brady, Olaf Witt, Ina Oehme

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Article number10039
JournalScientific Reports
Volume8
Issue number1
DOIs
StatePublished - Dec 1 2018

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Histone Deacetylases
Exocytosis
Neuroblastoma
DNA Repair
Doxorubicin
Lysosomes
Drug Therapy
Double-Stranded DNA Breaks
P-Glycoprotein
Treatment Failure
Drug Resistance
Organelles
DNA Damage
Neoplasms
Cell Survival
Homeostasis
Cell Death
Cell Line
Pharmaceutical Preparations

ASJC Scopus subject areas

  • General

Cite this

Ridinger, J., Koeneke, E., Kolbinger, F. R., Koerholz, K., Mahboobi, S., Hellweg, L., ... Oehme, I. (2018). Dual role of HDAC10 in lysosomal exocytosis and DNA repair promotes neuroblastoma chemoresistance. Scientific Reports, 8(1), [10039]. https://doi.org/10.1038/s41598-018-28265-5

Dual role of HDAC10 in lysosomal exocytosis and DNA repair promotes neuroblastoma chemoresistance. / Ridinger, Johannes; Koeneke, Emily; Kolbinger, Fiona R.; Koerholz, Katharina; Mahboobi, Siavosh; Hellweg, Lars; Gunkel, Nikolas; Miller, Aubry K.; Peterziel, Heike; Schmezer, Peter; Hamacher-Brady, Anne; Witt, Olaf; Oehme, Ina.

In: Scientific Reports, Vol. 8, No. 1, 10039, 01.12.2018.

Research output: Contribution to journalArticle

Ridinger, J, Koeneke, E, Kolbinger, FR, Koerholz, K, Mahboobi, S, Hellweg, L, Gunkel, N, Miller, AK, Peterziel, H, Schmezer, P, Hamacher-Brady, A, Witt, O & Oehme, I 2018, 'Dual role of HDAC10 in lysosomal exocytosis and DNA repair promotes neuroblastoma chemoresistance', Scientific Reports, vol. 8, no. 1, 10039. https://doi.org/10.1038/s41598-018-28265-5
Ridinger J, Koeneke E, Kolbinger FR, Koerholz K, Mahboobi S, Hellweg L et al. Dual role of HDAC10 in lysosomal exocytosis and DNA repair promotes neuroblastoma chemoresistance. Scientific Reports. 2018 Dec 1;8(1). 10039. https://doi.org/10.1038/s41598-018-28265-5
Ridinger, Johannes ; Koeneke, Emily ; Kolbinger, Fiona R. ; Koerholz, Katharina ; Mahboobi, Siavosh ; Hellweg, Lars ; Gunkel, Nikolas ; Miller, Aubry K. ; Peterziel, Heike ; Schmezer, Peter ; Hamacher-Brady, Anne ; Witt, Olaf ; Oehme, Ina. / Dual role of HDAC10 in lysosomal exocytosis and DNA repair promotes neuroblastoma chemoresistance. In: Scientific Reports. 2018 ; Vol. 8, No. 1.
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