Abstract
Cellular dormancy in colorectal cancer (CRC) significantly contributes to therapeutic resistance, tumor recurrence, and metastasis, resulting in poor prognosis. However, the underlying molecular mechanisms remain poorly understood. Here, we used spheroid culture combined with serum deprivation to enrich and identify dormancy-like CRC cells in vitro and characterized their dormancy-like phenotype by G0/G1 phase arrest, suppressed proliferation and radio-resistance. Compared to proliferative cells, dormancy-like CRC cells maintained similar tumor formation capacity but displayed higher PD-L1 expression level and enhanced migratory ability, indicating greater aggressiveness. Proteomics analysis revealed DDX21 was significantly downregulated in dormancy-like CRC cells, and analysis of clinical data showed an inverse correlation between DDX21 and PD-L1 in CRC patients. This is consistent with the findings that knocking down DDX21 markedly increased PD-L1 levels, suggesting a role for DDX21 in immune evasion. Importantly, overexpressing DDX21 reversed the radio-resistance of dormancy-like CRC cells. Mechanistically, DDX21 downregulation induced a dormancy-like phenotype via p38MAPK activation and AKT suppression to inhibit cellular growth. Furthermore, DDX21 bound to the NUCKS1 promoter, and its downregulation reduced NUCKS1 transcription, leading to elevated p27/p21 levels, which reinforced G0/G1 arrest. We also identified HERC2 as the E3 ligase mediating DDX21 degradation via K48/K63-linked polyubiquitination, dependent on the DDX21 helicase core domain. In conclusion, our findings establish DDX21 as a crucial regulator of dormancy-like phenotype in colorectal cancer cells and highlight its potential as a biomarker for dormancy-like tumor populations, radioresistance and poor clinical outcomes in CRC.
Similar content being viewed by others
Funding
This research was funded by the National Natural Science Foundation of China (Nos. 12375338, 12235004, 32171235, 12175044, 82173461).
Author information
Authors and Affiliations
Corresponding authors
Ethics declarations
Competing interests
The authors declare no competing interests.
Ethics statement
This study complied with the Declaration of Helsinki and the Basel Declaration. Protocols involving human subjects and their data were reviewed and approved by the Ethics Committee of the China-Japan Union Hospital of Jilin University (2022-KYYS-048), with informed consent obtained from all participants. All animal procedures were approved by the Animal Welfare and Ethics Committee of Fudan University and conducted in strict accordance with relevant guidelines (2023-FSYX-05JZS).
Additional information
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Edited by Professor Gennaro Ciliberto
Rights and permissions
Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.
About this article
Cite this article
Xiao, Y., He, M., Yao, H. et al. Ubiquitination of DDX21 by HERC2 induces a dormancy-like phenotype via the NUCKS1-p21/p27 axis to promote radio-resistance in colorectal cancer cells. Cell Death Dis (2026). https://doi.org/10.1038/s41419-026-08811-0
Received:
Revised:
Accepted:
Published:
DOI: https://doi.org/10.1038/s41419-026-08811-0
