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.
Highlights
Neuroblastoma, a neuroectodermally derived embryonic tumor and most common extracranial tumor of childhood, remains a major cause of cancer-related deaths in children, mostly due to systemic and resistant relapses.[1]
To decipher mechanisms controlled by HDAC11 in neuroblastoma cells, we assessed phenotypic appearance, intracellular adenosine triphosphate (ATP) content, and number of viable and dead cells following transient HDAC11 knockdown in BE(2)-C and IMR-32 cells
Our experiments show that HDAC11 depletion in neuroblastoma cells causes formation of aberrant mitotic spindle assemblies followed by increased cell death
Summary
Neuroblastoma, a neuroectodermally derived embryonic tumor and most common extracranial tumor of childhood, remains a major cause of cancer-related deaths in children, mostly due to systemic and resistant relapses.[1]. MYCN oncogene amplifications,[2,3] TERT activation by genomic rearrangements,[4,5] ATRX loss-of-function mutations/deletions[6] and germline/somatic activating ALK mutations[7–10] define patient subgroups at high risk for failing primary long-term remission despite aggressive multimodal treatment. Treatment for relapsed neuroblastoma and even first-line therapy for molecularly defined high-risk disease is currently undergoing a paradigm shift from classical cytotoxic agent combinations toward incorporating targeted drugs and immunotherapeutics into treatment schedules. 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]. BE(2)C and IMR-32 were chosen as representative cell lines for the high-risk neuroblastoma subtype characterized by MYCN. 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
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