Alternative polyadenylation in cancer: mechanisms, functions, and therapeutic potential.
8 affiliations
- 1Hunan Key Laboratory of Tumor Models and Individualized Medicine, The Second Xiangya Hospital of Central South University, Changsha, 410011, Hunan, China.
- 2Hunan Engineering Research Center of AI Medical Equipment, The Second Xiangya Hospital of Central South University, Changsha, 410011, Hunan, China.
- 3Department of Thoracic Surgery, the Second Xiangya Hospital, Central South University, Changsha, Hunan, China.
- 4Department of Orthopaedics, The Second Xiangya Hospital, Central South University, Changsha, 410011, Hunan, China.
- 5Department of Thoracic Surgery, the Second Xiangya Hospital, Central South University, Changsha, Hunan, China. [email protected].
- 6Hunan Key Laboratory of Tumor Models and Individualized Medicine, The Second Xiangya Hospital of Central South University, Changsha, 410011, Hunan, China. [email protected].
- 7Department of Orthopaedics, The Second Xiangya Hospital, Central South University, Changsha, 410011, Hunan, China. [email protected].
- 8Hunan Engineering Research Center of AI Medical Equipment, The Second Xiangya Hospital of Central South University, Changsha, 410011, Hunan, China. [email protected].
Abstract
Alternative polyadenylation (APA) is a pervasive post-transcriptional regulatory mechanism that generates transcript isoforms with distinct 3' untranslated regions, terminal exons, or coding potential, thereby influencing mRNA stability, translation, localization, and protein output. Rather than representing a uniform 3'UTR-shortening process, APA comprises heterogeneous 3'-end regulatory events, including tandem 3'UTR APA and upstream APA events such as intronic polyadenylation (IPA), which differ in mechanisms, detection strategies, functional consequences, and clinical interpretation. Dysregulated APA is increasingly recognized as an important contributor to cancer initiation and progression. Tandem 3'UTR APA can remove miRNA- or RNA-binding protein-mediated repression and enhance oncogenic transcript output, whereas upstream APA events, including IPA, can generate prematurely terminated RNAs, truncated proteins, soluble isoforms, or neoantigenic products. In this review, we summarize the classification and biological consequences of major APA events, as well as experimental and computational approaches for APA analysis. We then discuss regulatory mechanisms involving core 3'-end processing factors, RNA-binding proteins, splicing-polyadenylation coupling in upstream APA/IPA, transcription-associated regulation, and promoter-terminator communication. Functionally, aberrant APA contributes to proliferation, invasion and metastasis, metabolic reprogramming, tumor microenvironment remodeling, antitumor immunity, and immune escape. Finally, we highlight APA events, APA regulators, 3'UTR-based signatures, and upstream APA/IPA-derived products as emerging biomarkers and discuss small-molecule, RNA-based, and CRISPR-based strategies for targeting APA or 3'-end processing in cancer.
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BibTeX
@article{huang2026alternative,
title = {{Alternative polyadenylation in cancer: mechanisms, functions, and therapeutic potential.}},
author = {Yu Huang and Zhihong Li and Fenglei Yu and Lujuan Wang},
journal = {Molecular cancer},
year = {2026},
month = aug,
doi = {10.1186/s12943-026-02760-0},
url = {https://europepmc.org/article/MED/42958242},
note = {CC BY-NC-ND},
}
RIS
TY - JOUR
TI - Alternative polyadenylation in cancer: mechanisms, functions, and therapeutic potential.
AU - Yu Huang
AU - Zhihong Li
AU - Fenglei Yu
AU - Lujuan Wang
PY - 2026
DA - 2026/08/01
JO - Molecular cancer
DO - 10.1186/s12943-026-02760-0
UR - https://europepmc.org/article/MED/42958242
AB - Alternative polyadenylation (APA) is a pervasive post-transcriptional regulatory mechanism that generates transcript isoforms with distinct 3' untranslated regions, terminal exons, or coding potential, thereby influencing mRNA stability, translation, localization, and protein output. Rather than representing a uniform 3'UTR-shortening process, APA comprises heterogeneous 3'-end regulatory events, including tandem 3'UTR APA and upstream APA events such as intronic polyadenylation (IPA), which differ in mechanisms, detection strategies, functional consequences, and clinical interpretation. Dysregulated APA is increasingly recognized as an important contributor to cancer initiation and progression. Tandem 3'UTR APA can remove miRNA- or RNA-binding protein-mediated repression and enhance oncogenic transcript output, whereas upstream APA events, including IPA, can generate prematurely terminated RNAs, truncated proteins, soluble isoforms, or neoantigenic products. In this review, we summarize the classification and biological consequences of major APA events, as well as experimental and computational approaches for APA analysis. We then discuss regulatory mechanisms involving core 3'-end processing factors, RNA-binding proteins, splicing-polyadenylation coupling in upstream APA/IPA, transcription-associated regulation, and promoter-terminator communication. Functionally, aberrant APA contributes to proliferation, invasion and metastasis, metabolic reprogramming, tumor microenvironment remodeling, antitumor immunity, and immune escape. Finally, we highlight APA events, APA regulators, 3'UTR-based signatures, and upstream APA/IPA-derived products as emerging biomarkers and discuss small-molecule, RNA-based, and CRISPR-based strategies for targeting APA or 3'-end processing in cancer.
SN - 1476-4598
ER -