An integrated transcriptional and post-transcriptional regulatory circuit orchestrated by NUDT21 maintains the proliferation and survival of neuroblastoma
Abstract
Background: Neuroblastoma (NB) is the most prevalent pediatric solid tumor associated with a poor prognosis. While alternative polyadenylation (APA) is a key post-transcriptional regulatory mechanism in many cancers, its role in NB remains largely unexplored.
Methods: We used public expression profiles from NB and normal samples, along with single-cell transcriptomic data from our MYCN-transgenic mouse models, to screen NB-upregulated APA-related genes. Knockdown method was used to examine the function of NUDT21 in NB cells and in nude mice. RNA-seq and polyadenylation signal (PAS)-seq were performed to identify differentially expressed genes with APA events. Cleavage under targets and tagmentation (CUT&Tag) was used to analyze the transcriptional activation of downstream genes.
Results: NUDT21 was found substantially upregulated in NB, driven by NB master transcription factors (TFs) like MYCN. NUDT21 knockdown inhibited NB cell proliferation, induced cycle arrest and apoptosis in vitro, and suppressed xenograft growth in nude mice. Mechanistically, NUDT21 silencing triggered global APA remodeling, with approximately 85% of APA genes shifting to proximal poly(A) sites. Integrative PAS-seq and RNA-seq analyses revealed that NUDT21 regulated E2F target genes (eg, MKI67) via APA, promoting longer 3′ untranslated region (3′ UTR) isoforms to enhance mRNA stability and translation. The CUT&Tag analysis further indicated direct transcriptional regulation on E2F target genes by NUDT21 through promoter binding. This convergence of APA-mediated post-transcriptional regulation and transcriptional activation on the E2F network established a sophisticated oncogenic paradigm.
Conclusions: Our study identified NUDT21 as a critical driver of NB progression through both transcriptional and post-transcriptional mechanisms, laying the foundation for NUDT21-targeted NB therapies.
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BibTeX
@article{yang2026integrated,
title = {{An integrated transcriptional and post-transcriptional regulatory circuit orchestrated by NUDT21 maintains the proliferation and survival of neuroblastoma}},
author = {Yang Yang and Chunxia Shi and Jianwei Wang and Di Wu and Juanjuan Yu and Conglian Qiu and Tong Liu and Tiandan Li and Xingxing Wu and Xiaolu Li and Gen Li and Chun Yang and Hongli Yin and Yanling Chen and Lanlan Han and Shuiyan Wu and Yanfang Tao and Zimu Zhang and Jian Pan},
journal = {Neuro-Oncology},
year = {2026},
month = jul,
doi = {10.1093/neuonc/noag170},
url = {https://doi.org/10.1093/neuonc/noag170},
note = {CC BY-NC 4.0},
}
RIS
TY - JOUR
TI - An integrated transcriptional and post-transcriptional regulatory circuit orchestrated by NUDT21 maintains the proliferation and survival of neuroblastoma
AU - Yang Yang
AU - Chunxia Shi
AU - Jianwei Wang
AU - Di Wu
AU - Juanjuan Yu
AU - Conglian Qiu
AU - Tong Liu
AU - Tiandan Li
AU - Xingxing Wu
AU - Xiaolu Li
AU - Gen Li
AU - Chun Yang
AU - Hongli Yin
AU - Yanling Chen
AU - Lanlan Han
AU - Shuiyan Wu
AU - Yanfang Tao
AU - Zimu Zhang
AU - Jian Pan
PY - 2026
DA - 2026/07/27
JO - Neuro-Oncology
DO - 10.1093/neuonc/noag170
UR - https://doi.org/10.1093/neuonc/noag170
AB - Background: Neuroblastoma (NB) is the most prevalent pediatric solid tumor associated with a poor prognosis. While alternative polyadenylation (APA) is a key post-transcriptional regulatory mechanism in many cancers, its role in NB remains largely unexplored. Methods: We used public expression profiles from NB and normal samples, along with single-cell transcriptomic data from our MYCN-transgenic mouse models, to screen NB-upregulated APA-related genes. Knockdown method was used to examine the function of NUDT21 in NB cells and in nude mice. RNA-seq and polyadenylation signal (PAS)-seq were performed to identify differentially expressed genes with APA events. Cleavage under targets and tagmentation (CUT&Tag) was used to analyze the transcriptional activation of downstream genes. Results: NUDT21 was found substantially upregulated in NB, driven by NB master transcription factors (TFs) like MYCN. NUDT21 knockdown inhibited NB cell proliferation, induced cycle arrest and apoptosis in vitro, and suppressed xenograft growth in nude mice. Mechanistically, NUDT21 silencing triggered global APA remodeling, with approximately 85% of APA genes shifting to proximal poly(A) sites. Integrative PAS-seq and RNA-seq analyses revealed that NUDT21 regulated E2F target genes (eg, MKI67) via APA, promoting longer 3′ untranslated region (3′ UTR) isoforms to enhance mRNA stability and translation. The CUT&Tag analysis further indicated direct transcriptional regulation on E2F target genes by NUDT21 through promoter binding. This convergence of APA-mediated post-transcriptional regulation and transcriptional activation on the E2F network established a sophisticated oncogenic paradigm. Conclusions: Our study identified NUDT21 as a critical driver of NB progression through both transcriptional and post-transcriptional mechanisms, laying the foundation for NUDT21-targeted NB therapies.
SN - 1522-8517
SN - 1523-5866
ER -