Universität zu Köln

Thole, Theresa M., Lodrini, Marco, Fabian, Johannes, Wuenschel, Jasmin, Pfeil, Sebastian, Hielscher, Thomas, Kopp-Schneider, Annette, Heinicke, Ulrike, Fulda, Simone ORCID: 0000-0002-0459-6417, Witt, Olaf, Eggert, Angelika, Fischer, Matthias and Deubzer, Hedwig E. (2017). Neuroblastoma cells depend on HDAC11 for mitotic cell cycle progression and survival. Cell Death Dis., 8. LONDON: NATURE PUBLISHING GROUP. ISSN 2041-4889

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Abstract

The number of long-term survivors of high-risk neuroblastoma remains discouraging, with 10-year survival as low as 20%, despite decades of considerable international efforts to improve outcome. Major obstacles remain and include managing resistance to induction therapy, which causes tumor progression and early death in high-risk patients, and managing chemotherapy-resistant relapses, which can occur years after the initial diagnosis. Identifying and validating novel therapeutic targets is essential to improve treatment. Delineating and deciphering specific functions of single histone deacetylases in neuroblastoma may support development of targeted acetylome-modifying therapeutics for patients with molecularly defined high-risk neuroblastoma profiles. We show here that HDAC11 depletion in MYCN-driven neuroblastoma cell lines strongly induces cell death, mostly mediated by apoptotic programs. Genes necessary for mitotic cell cycle progression and cell division were most prominently enriched in at least two of three time points in whole-genome expression data combined from two cell systems, and all nine genes in these functional categories were strongly repressed, including CENPA, KIF14, KIF23 and RACGAP1. Enforced expression of one selected candidate, RACGAP1, partially rescued the induction of apoptosis caused by HDAC11 depletion. High-level expression of all nine genes in primary neuroblastomas significantly correlated with unfavorable overall and event-free survival in patients, suggesting a role in mediating the more aggressive biological and clinical phenotype of these tumors. Our study identified a group of cell cycle-promoting genes regulated by HDAC11, being both predictors of unfavorable patient outcome and essential for tumor cell viability. The data indicate a significant role of HDAC11 for mitotic cell cycle progression and survival of MYCN-amplified neuroblastoma cells, and suggests that HDAC11 could be a valuable drug target.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Thole, Theresa M. UNSPECIFIED UNSPECIFIED UNSPECIFIED Lodrini, Marco UNSPECIFIED UNSPECIFIED UNSPECIFIED Fabian, Johannes UNSPECIFIED UNSPECIFIED UNSPECIFIED Wuenschel, Jasmin UNSPECIFIED UNSPECIFIED UNSPECIFIED Pfeil, Sebastian UNSPECIFIED UNSPECIFIED UNSPECIFIED Hielscher, Thomas UNSPECIFIED UNSPECIFIED UNSPECIFIED Kopp-Schneider, Annette UNSPECIFIED UNSPECIFIED UNSPECIFIED Heinicke, Ulrike UNSPECIFIED UNSPECIFIED UNSPECIFIED Fulda, Simone UNSPECIFIED orcid.org/0000-0002-0459-6417 UNSPECIFIED Witt, Olaf UNSPECIFIED UNSPECIFIED UNSPECIFIED Eggert, Angelika UNSPECIFIED UNSPECIFIED UNSPECIFIED Fischer, Matthias UNSPECIFIED UNSPECIFIED UNSPECIFIED Deubzer, Hedwig E. UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-237989
DOI:	10.1038/cddis.2017.49
Journal or Publication Title:	Cell Death Dis.
Volume:	8
Date:	2017
Publisher:	NATURE PUBLISHING GROUP
Place of Publication:	LONDON
ISSN:	2041-4889
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language MESSENGER-RNA EXPRESSION; GENE-EXPRESSION; ACTIVATING MUTATIONS; PROGNOSTIC MARKER; BREAST-CANCER; ALK KINASE; IN-VITRO; KIF14; MYCN; INHIBITION Multiple languages Cell Biology Multiple languages
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/23798