PUBLICATION
Targeted inhibition of WIP1 and histone H3K27 demethylase activity synergistically suppresses neuroblastoma growth
- Authors
- Treis, D., Lundberg, K.I., Bell, N., Polychronopoulos, P.A., Tümmler, C., Åkerlund, E., Aliverti, S., Lilienthal, I., Pepich, A., Seashore-Ludlow, B., Sakaguchi, K., Kogner, P., Johnsen, J.I., Wickström, M.
- ID
- ZDB-PUB-250420-9
- Date
- 2025
- Source
- Cell Death & Disease 16: 318318 (Journal)
- Registered Authors
- Keywords
- none
- MeSH Terms
-
- Drug Synergism
- Apoptosis/drug effects
- Humans
- Cell Proliferation/drug effects
- Cell Line, Tumor
- Xenograft Model Antitumor Assays
- Histones*/metabolism
- Gene Expression Regulation, Neoplastic/drug effects
- Zebrafish
- Protein Phosphatase 2C*/antagonists & inhibitors
- Protein Phosphatase 2C*/genetics
- Protein Phosphatase 2C*/metabolism
- Tumor Suppressor Protein p53/metabolism
- Pyrimidines
- Histone Demethylases*/antagonists & inhibitors
- Histone Demethylases*/metabolism
- Jumonji Domain-Containing Histone Demethylases*/antagonists & inhibitors
- Jumonji Domain-Containing Histone Demethylases*/metabolism
- Animals
- Benzazepines/pharmacology
- Neuroblastoma*/drug therapy
- Neuroblastoma*/enzymology
- Neuroblastoma*/genetics
- Neuroblastoma*/pathology
- PubMed
- 40253363 Full text @ Cell Death Dis.
Citation
Treis, D., Lundberg, K.I., Bell, N., Polychronopoulos, P.A., Tümmler, C., Åkerlund, E., Aliverti, S., Lilienthal, I., Pepich, A., Seashore-Ludlow, B., Sakaguchi, K., Kogner, P., Johnsen, J.I., Wickström, M. (2025) Targeted inhibition of WIP1 and histone H3K27 demethylase activity synergistically suppresses neuroblastoma growth. Cell Death & Disease. 16:318318.
Abstract
High-risk neuroblastoma frequently exhibits segmental gain of chromosome 17q, including the locus of PPM1D, which encodes the phosphatase WIP1, a regulator of p53 activity, DNA repair, and apoptosis. High expression of PPM1D is correlated to poor prognosis, and genetic or pharmacologic inhibition of WIP1 suppresses neuroblastoma growth. Here, we show that combining drugs that target WIP1 and H3K27 demethylation induces synergistic cytotoxicity in neuroblastoma. We screened 527 different compounds together with inhibitors of WIP1 and identified a strong cytotoxic synergism between the WIP1 inhibitor SL-176 and GSK-J4, a specific inhibitor of the H3K27 demethylase JMJD3. Viability assays in neuroblastoma cell lines and treatment of tumor spheroids confirmed the synergistic effect of combining SL-176 with GSK-J4. Immunoblot experiments demonstrated a marked effect on WIP1 downstream targets and apoptosis markers, while qPCR showed a synergistic upregulation of p53 downstream targets PUMA and p21. RNA sequencing revealed a vast number of differentially expressed genes, suggesting a pervasive effect of this drug combination on transcription, with enrichment of pathways involved in DNA damage response. Finally, this drug combination was confirmed to reduce tumor growth in zebrafish xenograft experiments. In conclusion, the combination of the WIP1 inhibitor SL-176 and the epigenetic modifier GSK-J4 induces synergistic cytotoxicity in neuroblastoma cells by potentiating p53 downstream effects.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping