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ZNF334 suppresses colorectal cancer by inducing cell cycle arrest through UCHL1/ZYG11A-mediated perturbation of Cyclin B1–CDK1 complex
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DOI：10.1016/j.gendis.2026.102381.png)
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Abstract
En 中文
A deregulated cell cycle is a hallmark of malignancies, including colorectal cancer (CRC), where over 80% of cases involve inactivation of tumor suppressor genes. However, how tumor suppressor genes regulate the cell cycle to enhance chemotherapy response remains less understood. In this study, we identified ZNF334 as a novel tumor suppressor gene in CRC that is frequently down-regulated in tumors due to hypermethylation. Using in vitro and in vivo models, alongside human CRC organoids, we demonstrated that ZNF334 exerted significant anti-tumor function and potentiated chemotherapy. Mechanistically, integrative analysis of flow cytometry, bulk RNA-sequencing, quantitative proteomics, chromatin immunoprecipitation–quantitative PCR, and co-immunoprecipitation assays revealed that ZNF334 induced prominent cell cycle arrest in G2/M phase via reducing the Cyclin B1–CDK1 kinase activity. Specifically, ZNF334 transcriptionally activated UCHL1 to disrupt the Cyclin B1–CDK1 interaction and up-regulated ZYG11A to boost the ubiquitin-mediated degradation of Cyclin B1. Moreover, we found that 5-fluorouracil treatment markedly raised ZNF334 expression, which in turn triggered G2/M arrest and sensitized CRC cells to 5-fluorouracil and other chemotherapeutic drugs. In summary, our study uncovered a previously unrecognized ZNF334–UCHL1/ZYG11A regulatory axis that governs the cell cycle machinery, highlighting ZNF334 as a potential therapeutic target and a biomarker for predicting chemotherapy response in CRC.
Keywords:
Cell cycle
Colorectal cancer
Ubiquitination
ZNF334
Chemotherapy
Journal
G
IF:
9.4
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304
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