Targeting Group 3 Medulloblastoma by the Anti-PRUNE-1 and Anti-LSD1/KDM1A Epigenetic Molecules.

Autor: Bibbò F; Department of Molecular Medicine and Medical Biotechnological DMMBM, University Federico II of Naples, 80131 Naples, Italy.; CEINGE Biotecnologie Avanzate 'Franco Salvatore', 80131 Naples, Italy., Asadzadeh F; CEINGE Biotecnologie Avanzate 'Franco Salvatore', 80131 Naples, Italy.; SEMM European School of Molecular Medicine, 20139 Milan, Italy., Boccia A; CEINGE Biotecnologie Avanzate 'Franco Salvatore', 80131 Naples, Italy., Sorice C; CEINGE Biotecnologie Avanzate 'Franco Salvatore', 80131 Naples, Italy., Bianco O; CEINGE Biotecnologie Avanzate 'Franco Salvatore', 80131 Naples, Italy., Saccà CD; Department of Biology, University Federico II of Naples, 80138 Naples, Italy., Majello B; Department of Biology, University Federico II of Naples, 80138 Naples, Italy., Donofrio V; Department of Pathology, Santobono-Pausilipon Children's Hospital, AORN, 80129 Naples, Italy., Bifano D; Department of Pathology, Santobono-Pausilipon Children's Hospital, AORN, 80129 Naples, Italy., De Martino L; Pediatric Neuro-Oncology, Santobono-Pausilipon Children's Hospital, AORN, 80129 Naples, Italy., Quaglietta L; Pediatric Neuro-Oncology, Santobono-Pausilipon Children's Hospital, AORN, 80129 Naples, Italy., Cristofano A; Pediatric Neuroradiology, Santobono-Pausilipon Children's Hospital, AORN, 80129 Naples, Italy., Covelli EM; Pediatric Neuroradiology, Santobono-Pausilipon Children's Hospital, AORN, 80129 Naples, Italy., Cinalli G; Pediatric Neurosurgery, Santobono-Pausilipon Children's Hospital, AORN, 80129 Naples, Italy., Ferrucci V; Department of Molecular Medicine and Medical Biotechnological DMMBM, University Federico II of Naples, 80131 Naples, Italy.; CEINGE Biotecnologie Avanzate 'Franco Salvatore', 80131 Naples, Italy., De Antonellis P; Department of Molecular Medicine and Medical Biotechnological DMMBM, University Federico II of Naples, 80131 Naples, Italy.; CEINGE Biotecnologie Avanzate 'Franco Salvatore', 80131 Naples, Italy., Zollo M; Department of Molecular Medicine and Medical Biotechnological DMMBM, University Federico II of Naples, 80131 Naples, Italy.; CEINGE Biotecnologie Avanzate 'Franco Salvatore', 80131 Naples, Italy.; DAI Medicina di Laboratorio e Trasfusionale, 'AOU Federico II Policlinico', 80131 Naples, Italy.
Jazyk: angličtina
Zdroj: International journal of molecular sciences [Int J Mol Sci] 2024 Mar 31; Vol. 25 (7). Date of Electronic Publication: 2024 Mar 31.
DOI: 10.3390/ijms25073917
Abstrakt: Medulloblastoma (MB) is a highly malignant childhood brain tumor. Group 3 MB (Gr3 MB) is considered to have the most metastatic potential, and tailored therapies for Gr3 MB are currently lacking. Gr3 MB is driven by PRUNE-1 amplification or overexpression. In this paper, we found that PRUNE-1 was transcriptionally regulated by lysine demethylase LSD1/KDM1A. This study aimed to investigate the therapeutic potential of inhibiting both PRUNE-1 and LSD1/KDM1A with the selective inhibitors AA7.1 and SP-2577, respectively. We found that the pharmacological inhibition had a substantial efficacy on targeting the metastatic axis driven by PRUNE-1 (PRUNE-1-OTX2-TGFβ-PTEN) in Gr3 MB. Using RNA seq transcriptomic feature data in Gr3 MB primary cells, we provide evidence that the combination of AA7.1 and SP-2577 positively affects neuronal commitment, confirmed by glial fibrillary acidic protein (GFAP)-positive differentiation and the inhibition of the cytotoxic components of the tumor microenvironment and the epithelial-mesenchymal transition (EMT) by the down-regulation of N-Cadherin protein expression. We also identified an impairing action on the mitochondrial metabolism and, consequently, oxidative phosphorylation, thus depriving tumors cells of an important source of energy. Furthermore, by overlapping the genomic mutational signatures through WES sequence analyses with RNA seq transcriptomic feature data, we propose in this paper that the combination of these two small molecules can be used in a second-line treatment in advanced therapeutics against Gr3 MB. Our study demonstrates that the usage of PRUNE-1 and LSD1/KDM1A inhibitors in combination represents a novel therapeutic approach for these highly aggressive metastatic MB tumors.
Databáze: MEDLINE
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