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.

MYCN acts as a direct co-regulator of p53 in MYCN amplified neuroblastoma

“…Functional annotation analysis of p53 responsive genes validated previous demonstrations that MYCN represses p53 apoptotic genes and increases proliferation and mitosis related genes (Figure 4C, 4D ), Interestingly, we found a group of genes only modulated by p53 when MYCN levels were high. The top functional clusters of these genes included DNA metabolism, cell division, and chromosome segregation ( Supplementary Figure 1-2 ) [ 22 , 23 ]. These genes were not modulated by p53 in the absence of MYCN.…”

GSK3β-dependent cyclin D1 and cyclin E1 degradation is indispensable for NVP-BEZ235 induced G0/G1 arrest in neuroblastoma cells

“…4,5 The 10-year survival rate of high-risk neuroblastoma patients is as low as 20% despite decades of the considerable advances in diagnostic methods and the development in therapeutic treatment. 6 Due to major obstacles like MYCN oncogene amplifications and germline or somatic activating ALK mutations, chemotherapy resistance and poor prognosis subsequently occur to patients. 7 Therefore, the identification and validation of novel therapeutic agents remain an effective strategy to further improve survival and long-term quality of life of patients.…”

Neuroblastoma: Genetic, Epigenetic Mechanisms and Targeted Therapy Approaches: Review

“…HDAC11, tedavi için umut veren bir hedef olarak görülebil-mektedir. 84 HDAC8 inhibisyonu ve miR-137 eksBakiye GÖKER BAĞCA ve ark. Turkiye Klinikleri J Neur 2017;12(2):25-39 34 ŞEKİL 2: Nöroblastomda rol oynayan genetik ve epigenetik mekanizmalar.…”