Open Access

ARTICLE

NUDT21 Functions as a Pro-Tumorigenic Gene in Colorectal Cancer by Upregulating the TAZ Protein Expression

Xiaojian Chen^1,2,#, Zhujiang Dai^1,#, Qiang Wang³, Wei Chen¹, Yun Liu^1,*, Zhongchuan Wang^1,*

1 Department of Colorectal and Anal Surgery, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, 200092, China
2 Department of Thoracic Surgery, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200011, China
3 Department of Gastrointestinal Surgery, Tiantai People’s Hospital, Taizhou, 317200, China

* Corresponding Authors: Yun Liu. Email: ; Zhongchuan Wang. Email:
# These authors have contributed equally to this work

(This article belongs to the Special Issue: Genetic Biomarkers of Cancer: Insights into Molecular and Cellular Mechanisms)

BIOCELL 2025, 49(3), 503-518. https://doi.org/10.32604/biocell.2025.059286

Received 03 October 2024; Accepted 20 February 2025; Issue published 01 April 2025

Abstract

Background: Nudix Hydrolase 21 (NUDT21) is crucial for the regulation of alternative polyadenylation, with its reduced expression frequently resulting in a shortened mRNA 3^′ untranslated region (UTR), thereby enhancing the protein levels of downstream genes. Although NUDT21 is widely recognized for its tumor-suppressive function in various cancers, its involvement in colorectal cancer (CRC) remains poorly understood. Methods: The expression of NUDT21 in CRC and adjacent normal tissues was analyzed through qPCR, Western blot, and immunohistochemistry (IHC). Additionally, we investigated the correlation between NUDT21 expression and patient prognosis. With Cell Counting Kit-8 assay and Transwell assay, we detected the exact role of NUDT21 in the development and progress of CRC. We used RNA-Seq analysis to explore the downstream target gene of NUDT21. Meanwhile, DaPars analysis revealed the Hippo pathway as a critical pathway in CRC progress. Western blotting and luciferase assays were used to investigate the specific mechanisms by which NUDT21 regulates the Hippo pathway. In addition, the interaction between NUDT21 and TAZ was confirmed by co-immunoprecipitation and the correlation between the two expressions was verified by IHC. Results: In CRC, elevated NUDT21 expression has been identified as a predictor of poor prognosis, as well as a promoter of CRC cell proliferation and migration. Combined with RNA-seq and DaPars analyses, we identified the Hippo pathway as an important downstream target of NUDT21 in CRC. NUDT21 knockdown significantly downregulated the YAP, TAZ, and TEAD1 protein levels. Mechanistically, shortening of the 3^′UTR of TAZ by NUDT21 knockdown suppressed TAZ protein expression. A positive correlation was observed between NUDT21 and TAZ proteins in CRC. Conclusion: NUDT21 plays a pro-tumorigenic role in CRC by upregulating TAZ protein expression, revealing a new regulatory mechanism of the Hippo pathway and providing insight into the biological effect of mRNA 3^′UTR shortening.

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Supplementary Material

Supplementary Material File

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