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000136790 1001_ $$0P:(DE-He78)53112ef656923758316e7079710bc988$$aRidinger, Johannes$$b0$$eFirst author$$udkfz
000136790 245__ $$aDual role of HDAC10 in lysosomal exocytosis and DNA repair promotes neuroblastoma chemoresistance.
000136790 260__ $$aLondon$$bNature Publishing Group$$c2018
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000136790 520__ $$aDrug 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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000136790 7001_ $$0P:(DE-He78)700a3a9eaae170adaad6cfbd3d696f93$$aKoeneke, Emily$$b1$$udkfz
000136790 7001_ $$0P:(DE-He78)556dfbcf5489cf998946e2b316deca4d$$aKolbinger, Fiona$$b2$$udkfz
000136790 7001_ $$0P:(DE-HGF)0$$aKoerholz, Katharina$$b3
000136790 7001_ $$aMahboobi, Siavosh$$b4
000136790 7001_ $$0P:(DE-HGF)0$$aHellweg, Lars$$b5
000136790 7001_ $$0P:(DE-HGF)0$$aGunkel, Nikolas$$b6
000136790 7001_ $$0P:(DE-He78)f0af962ddbc82430e947390b2f3f6e49$$aMiller, Aubry$$b7$$udkfz
000136790 7001_ $$0P:(DE-He78)2727b5cb63b52d0137d4f4e8f110ee7e$$aPeterziel, Heike$$b8$$udkfz
000136790 7001_ $$0P:(DE-He78)141ce740f5d881812d2675147b72ecaf$$aSchmezer, Peter$$b9$$udkfz
000136790 7001_ $$aHamacher-Brady, Anne$$b10
000136790 7001_ $$0P:(DE-He78)143af26de9d57bf624771616318aaf7c$$aWitt, Olaf$$b11$$udkfz
000136790 7001_ $$0P:(DE-He78)908367a659dea9e28dac34592b3c46e5$$aOehme, Ina$$b12$$eLast author$$udkfz
000136790 773__ $$0PERI:(DE-600)2615211-3$$a10.1038/s41598-018-28265-5$$gVol. 8, no. 1, p. 10039$$n1$$p10039$$tScientific reports$$v8$$x2045-2322$$y2018
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