Neuroblastoma cells depend on HDAC11 for mitotic cell cycle progression and survival

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.

...Cell Death Dis Cell Death Dis Cell Death & Disease 2041-4889 Nature Publishing Group 28252645 5386552 cddis201749 10.1038/cddis.2017.49 Original Article Neuroblastoma cells depend on HDAC11 for mitotic cell cycle progression and survival HDAC11 in neuroblastoma Thole Theresa M 1 2 3 Lodrini Marco 1 3 Fabian Johannes 3 11 Wuenschel Jasmin 1 3 Pfeil Sebastian 1 Hielscher Thomas 4 http://orcid.org/0000-0003-1277-310X Kopp-Schneider Annette 4 Heinicke Ulrike 5 Fulda Simone 5 6 7 Witt Olaf 2 3

.... 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. Neuroblastoma, a neuroectodermally derived embryonic tumor and

... of acetylome-modifying drugs. MYCN was shown to recruit HDAC1/2/3/5 to promoter sites to repress transcription in neuroblastoma cells, 18 , 19 , 20 , 21 whereas HDAC8 and HDAC10 inhibit differentiation and promote autophagy-mediated survival in a MYCN -independent manner. 22 , 23 Gao et al. 24 identified and characterized HDAC11 in 2002, the only class IV HDAC family member identified to date, which is located within the ~25kb region of chromosome 3p25.1. Expression of the FLAG-tagged 347 amino acid open reading frame in human embryonic kidney 293 cells, demonstrated the protein primarily localizes to the nucleus and is capable of deacetylating a synthetic peptide derived from histone H4. 24 Subsequent studies in recent years have shed light on the role of HDAC11 in health and disease. 25 Here we aimed to assess the significance of HDAC11 expression for neuroblastoma biology, which is as yet unknown. We recently showed that HDAC11 plays an important role in controlling proliferation in

... doxorubicin. 28 IMR-32 cells harbor a partial ALK amplification, resulting in constitutive ALK activity leading to uncontrolled proliferation. 29 We assessed the effect of HDAC11 depletion on phenotype in these two neuroblastoma cell models and performed whole-genome expression profiling to decipher the pathways triggering the HDAC11 depletion phenotype in neuroblastoma cells. Results HDAC11 depletion in neuroblastoma cells triggers cell death preceded by aberrant mitotic spindle assemblies To decipher

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Gene: HDAC11 - histone deacetylase 11 - (NCBI)

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