Language
English
Publication Date
12-27-2024
Journal
Journal of Translational Medicine
DOI
10.1186/s12967-024-05956-4
PMID
39731187
PMCID
PMC11673900
PubMedCentral® Posted Date
12-27-2024
PubMedCentral® Full Text Version
Post-print
Abstract
Background: Neuroblastoma (NB), the most prevalent solid tumor in children, arises from sympathetic nervous system and accounts for 15% of pediatric cancer mortality. This malignancy exhibits substantial genetic and clinical heterogeneity, thus complicating treatment strategies. Poly(ADP-ribose) polymerase 1 (PARP1), a key enzyme catalyzing polyADP-ribosylation (PARylation), plays critical roles in various cellular processes, and contributes to tumorigenesis and aggressiveness. However, the functions and regulatory mechanisms of PARP1 in NB progression still remain to be determined.
Methods: The association of PARP1 expression with NB patients' survival was analyzed by mining of R2 database. Western blotting, reverse transcription-polymerase chain reaction, MTT colorimetric, soft agar, and matrigel invasion assays were utilized to assess PARP1 expression and its effects on aggressiveness of NB cell lines. Chromatin immunoprecipitation (ChIP) sequencing and ChIP assays were employed to investigate the binding of Yin Yang 1 (YY1) to PARP1 promoter. Protein interactions were explored by BioGRID database analysis, molecular docking, and co-immunoprecipitation assay. RNA sequencing and crosslinking-immunoprecipitation high throughput sequencing datasets were used to identify precursor mRNA splicing targets of non-POU domain containing octamer binding protein (NONO).
Results: High PARP1 expression was associated with poor survival of NB patients. PARP1 over-expression enhanced the proliferation and invasion of NB cell lines, confirming its oncogenic roles. YY1 was identified as a key transcriptional regulator facilitating PARP1 expression. Additionally, PARP1 interacted with NONO to induce its PARylation, resulting in stabilization of NONO protein via preventing ubiquitin-mediated degradation. NONO facilitated the splicing and mRNA maturation of target genes a disintegrin and metalloproteinase domain 8 (ADAM8) and testis-expressed gene 14 (TEX14) in a PARylation-dependent manner. Rescue experiments indicated that YY1 facilitated PARP1-mediated PARylation of NONO and subsequent mRNA maturation of ADAM8 and TEX14 in NB cells. In clinical NB cases, high expression of YY1, PARP1, NONO, ADAM8, or TEX14 was associated with poor survival of patients.
Conclusions: These findings indicate that YY1 drives PARP1 expression essential for PARylation of NONO in mRNA maturation during NB progression.
Keywords
Humans, Poly (ADP-Ribose) Polymerase-1, Neuroblastoma, Cell Line, Tumor, YY1 Transcription Factor, RNA, Messenger, Gene Expression Regulation, Neoplastic, Disease Progression, RNA-Binding Proteins, Promoter Regions, Genetic, Protein Binding, Cell Proliferation, Neuroblastoma, Poly(ADP-ribose) polymerase 1, Yin Yang 1, Non-POU domain containing octamer binding protein, Transcriptional regulation, Protein PARylation, MRNA maturation
Published Open-Access
yes
Recommended Citation
Yang, Chunhui; Qu, Jiaying; Cheng, Yang; et al., "YY1 Drives PARP1 Expression Essential for PARylation of Nono in mRNA Maturation During Neuroblastoma Progression" (2024). Faculty, Staff and Students Publications. 8271.
https://digitalcommons.library.tmc.edu/baylor_docs/8271