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

Sci Rep. 2018 Jul 3;8(1):10039. doi: 10.1038/s41598-018-28265-5.

Johannes Ridinger ¹ ² ³, Emily Koeneke ¹ ² ⁴, Fiona R Kolbinger ¹ ², Katharina Koerholz ¹ ², Siavosh Mahboobi ⁵, Lars Hellweg ⁶, Nikolas Gunkel ⁶, Aubry K Miller ⁶, Heike Peterziel ¹ ², Peter Schmezer ⁷, Anne Hamacher-Brady ⁸, Olaf Witt ¹ ² ⁹, Ina Oehme ¹⁰ ¹¹

Affiliations

1 Preclinical Program, Hopp Children's Cancer Center at NCT Heidelberg (KiTZ), Heidelberg, Germany.
2 Clinical Cooperation Unit Pediatric Oncology, German Cancer Research Center (DKFZ), and German Cancer Consortium (DKTK), Im Neuenheimer Feld 280, 69120, Heidelberg, Germany.
3 Faculty of Biosciences, University of Heidelberg, Heidelberg, Germany.
4 University of Heidelberg, Heidelberg, Germany.
5 Institute of Pharmacy, University of Regensburg, Regensburg, Germany.
6 Research Group Cancer Drug Development, German Cancer Research Center, Heidelberg, Germany.
7 Division of Epigenomics and Cancer Risk Factors, German Cancer Research Center, Heidelberg, Germany.
8 Johns Hopkins University, Bloomberg School of Public Health, Baltimore, United States.
9 Department of Pediatric Oncology, Hematology and Immunology, University Hospital Heidelberg, Heidelberg, Germany.
10 Preclinical Program, Hopp Children's Cancer Center at NCT Heidelberg (KiTZ), Heidelberg, Germany. i.oehme@dkfz.de.
11 Clinical Cooperation Unit Pediatric Oncology, German Cancer Research Center (DKFZ), and German Cancer Consortium (DKTK), Im Neuenheimer Feld 280, 69120, Heidelberg, Germany. i.oehme@dkfz.de.

PMID: 29968769 DOI: 10.1038/s41598-018-28265-5

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.

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