The landscape and clinical relevance of intronic polyadenylation in human cancers

Xiaomeng Cheng; Guanghui Jiang; Xiaolan Zhou; Jing Wang; Zhaozhao Zhao; Jiayu Zhang; Ting Ni

doi:10.1016/j.jgg.2024.04.014

Volume 51 Issue 10

Oct. 2024

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Article Navigation > Journal of Genetics and Genomics > 2024 > 51(10): 1030-1039

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The landscape and clinical relevance of intronic polyadenylation in human cancers

doi: 10.1016/j.jgg.2024.04.014

a. State Key Laboratory of Genetic Engineering, National Clinical Research Center for Aging and Medicine, Huashan Hospital, Collaborative Innovation Center of Genetics and Development, Human Phenome Institute, Center for Evolutionary Biology, Shanghai Engineering Research Center of Industrial Microorganisms, School of Life Sciences, Fudan University, Shanghai 200438, China;
b. MOE Key Laboratory of Contemporary Anthropology, School of Life Sciences, Fudan University, Shanghai 200438, China;
c. State Key Laboratory of Reproductive Regulation and Breeding of Grassland Livestock, Institutes of Biomedical Sciences, School of Life Sciences, Inner Mongolia University, Hohhot, Inner Mongolia 010070, China

Funds:

This work was financially supported by the National Natural Science Foundation of China (92249302, 32370592) and the National Key Research and Development Program of China (2023YFC3603300, 2021YFA0909300).

Received Date: 2024-01-09
Accepted Date: 2024-04-25
Rev Recd Date: 2024-04-07

Available Online: 2025-06-06

Publish Date: 2024-05-11

Abstract

Abstract

Intronic polyadenylation (IPA) is an RNA 3′ end processing event which has been reported to play important roles in cancer development. However, the comprehensive landscape of IPA events across various cancer types is lacking. Here, we apply IPAFinder to identify and quantify IPA events in 10,383 samples covering all 33 cancer types from The Cancer Genome Atlas (TCGA) project. We identify a total of 21,835 IPA events, almost half of which are ubiquitously expressed. We identify 2761 unique dynamically changed IPA events across cancer types. Furthermore, we observe 8855 non-redundant clinically relevant IPA events, which could potentially be used as prognostic indicators. Our analysis also reveals that dynamic IPA usage within cancer signaling pathways may affect drug response. Finally, we develop a user-friendly data portal, IPACancer Atlas (http://www.tingni-lab.com/Pancan_IPA/), to search and explore IPAs in cancer.
- Intronic polyadenylation,
- Cancer,
- Single nucleotide variant,
- Drug sensitivity,
- Database

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References

Agarwal, S., Behring, M., Hale, K., Al Diffalha, S., Wang, K., Manne, U.,Varambally, S., 2019. Mthfd1l, a folate cycle enzyme, is involved in progression of colorectal cancer. Transl. Oncol. 12, 1461-1467.

Bailey, T.L.,Elkan, C., 1994. Fitting a mixture model by expectation maximization to discover motifs in biopolymers. Proc. Int. Conf. Intell. Syst. Mol. Biol. 2, 28-36.

Baughn, M.W., Melamed, Z., Lopez-Erauskin, J., Beccari, M.S., Ling, K., Zuberi, A., Presa, M., Gonzalo-Gil, E., Maimon, R., Vazquez-Sanchez, S., et al., 2023. Mechanism of stmn2 cryptic splice-polyadenylation and its correction for tdp-43 proteinopathies. Science 379, 1140-1149.

Berkovits, B.D.,Mayr, C., 2015. Alternative 3' utrs act as scaffolds to regulate membrane protein localization. Nature 522, 363-367.

Bogard, N., Linder, J., Rosenberg, A.B.,Seelig, G., 2019. A deep neural network for predicting and engineering alternative polyadenylation. Cell 178, 91-106.e123.

de Martin Garrido, N.,Aylett, C.H.S., 2020. Nutrient signaling and lysosome positioning crosstalk through a multifunctional protein, folliculin. Front. Cell Dev. Biol. 8, 108.

Diesh, C., Stevens, G.J., Xie, P., De Jesus Martinez, T., Hershberg, E.A., Leung, A., Guo, E., Dider, S., Zhang, J., Bridge, C., et al., 2023. Jbrowse 2: A modular genome browser with views of synteny and structural variation. Genome Biol. 24, 74.

Dubbury, S.J., Boutz, P.L.,Sharp, P.A., 2018. Cdk12 regulates DNA repair genes by suppressing intronic polyadenylation. Nature 564, 141-145.

Dunlop, E.A., Seifan, S., Claessens, T., Behrends, C., Kamps, M.A.F., Rozycka, E., Kemp, A.J., Nookala, R.K., Blenis, J., Coull, B.J., et al., 2014. Flcn, a novel autophagy component, interacts with gabarap and is regulated by ulk1 phosphorylation. Autophagy 10, 1749-1760.

Ehrmann, J.F., Grabarczyk, D.B., Heinke, M., Deszcz, L., Kurzbauer, R., Hudecz, O., Shulkina, A., Gogova, R., Meinhart, A., Versteeg, G.A., et al., 2023. Structural basis for regulation of apoptosis and autophagy by the birc6/smac complex. Science 379, 1117-1123.

Elton, T.S., Hernandez, V.A., Carvajal-Moreno, J., Wang, X., Ipinmoroti, D.,Yalowich, J.C., 2022. Intronic polyadenylation in acquired cancer drug resistance circumvented by utilizing crispr/cas9 with homology-directed repair: the tale of human DNA topoisomerase iiα. Cancers (Basel) 14.

Faber, A.C., Coffee, E.M., Costa, C., Dastur, A., Ebi, H., Hata, A.N., Yeo, A.T., Edelman, E.J., Song, Y., Tam, A.T., et al., 2014. Mtor inhibition specifically sensitizes colorectal cancers with kras or braf mutations to bcl-2/bcl-xl inhibition by suppressing mcl-1. Cancer Discov. 4, 42-52.

Geeleher, P., Zhang, Z., Wang, F., Gruener, R.F., Nath, A., Morrison, G., Bhutra, S., Grossman, R.L.,Huang, R.S., 2017. Discovering novel pharmacogenomic biomarkers by imputing drug response in cancer patients from large genomics studies. Genome Res. 27, 1743-1751.

Gong, J., Li, Y., Liu, C.J., Xiang, Y., Li, C., Ye, Y., Zhang, Z., Hawke, D.H., Park, P.K., Diao, L., et al., 2017. A pan-cancer analysis of the expression and clinical relevance of small nucleolar rnas in human cancer. Cell Rep. 21, 1968-1981.

Gruber, A.J.,Zavolan, M., 2019. Alternative cleavage and polyadenylation in health and disease. Nat. Rev. Genet. 20, 599-614.

Herrmann, C.J., Schmidt, R., Kanitz, A., Artimo, P., Gruber, A.J.,Zavolan, M., 2020. Polyasite 2.0: a consolidated atlas of polyadenylation sites from 3' end sequencing. Nucleic Acids Res. 48, D174-d179.

Insco, M.L., Abraham, B.J., Dubbury, S.J., Kaltheuner, I.H., Dust, S., Wu, C., Chen, K.Y., Liu, D., Bellaousov, S., Cox, A.M., et al., 2023. Oncogenic cdk13 mutations impede nuclear rna surveillance. Science 380, eabn7625.

Kurozumi, S., Joseph, C., Sonbul, S., Gorringe, K.L., Pigera, M., Aleskandarany, M.A., Diez-Rodriguez, M., Nolan, C.C., Fujii, T., Shirabe, K., et al., 2018. Clinical and biological roles of kelch-like family member 7 in breast cancer: a marker of poor prognosis. Breast Cancer Res. Treat. 170, 525-533.

Lee, S.H., Singh, I., Tisdale, S., Abdel-Wahab, O., Leslie, C.S.,Mayr, C., 2018. Widespread intronic polyadenylation inactivates tumour suppressor genes in leukaemia. Nature 561, 127-131.

Li, A., Zhang, J.,Zhou, Z., 2014. Plek: a tool for predicting long non-coding rnas and messenger rnas based on an improved k-mer scheme. BMC Bioinformatics 15, 311.

Li, H., Fu, X., Yao, F., Tian, T., Wang, C.,Yang, A., 2019. Mthfd1l-mediated redox homeostasis promotes tumor progression in tongue squamous cell carcinoma. Front. Oncol. 9, 1278.

Lotz, C.,Lamour, V., 2020. The interplay between DNA topoisomerase 2α post-translational modifications and drug resistance. Cancer Drug Resist. 3, 149-160.

Low, C.G., Luk, I.S., Lin, D., Fazli, L., Yang, K., Xu, Y., Gleave, M., Gout, P.W.,Wang, Y., 2013. Birc6 protein, an inhibitor of apoptosis: role in survival of human prostate cancer cells. PLoS One 8, e55837.

Ma, X., Cheng, S., Ding, R., Zhao, Z., Zou, X., Guang, S., Wang, Q., Jing, H., Yu, C., Ni, T., et al., 2023. Ipaqtl-atlas: an atlas of intronic polyadenylation quantitative trait loci across human tissues. Nucleic Acids Res. 51, D1046-d1052.

Mitschka, S.,Mayr, C., 2022. Context-specific regulation and function of mrna alternative polyadenylation. Nat. Rev. Mol. Cell Biol. 23, 779-796.

Quereda, V., Bayle, S., Vena, F., Frydman, S.M., Monastyrskyi, A., Roush, W.R.,Duckett, D.R., 2019. Therapeutic targeting of cdk12/cdk13 in triple-negative breast cancer. Cancer Cell 36, 545-558.e547.

Ren, J., Shi, M., Liu, R., Yang, Q.H., Johnson, T., Skarnes, W.C.,Du, C., 2005. The birc6 (bruce) gene regulates p53 and the mitochondrial pathway of apoptosis and is essential for mouse embryonic development. Proc. Natl. Acad. Sci. U. S. A. 102, 565-570.

Rossi, A.,Kontarakis, Z., 2022. Beyond mendelian inheritance: genetic buffering and phenotype variability. Phenomics 2, 79-87.

Sandberg, R., Neilson, J.R., Sarma, A., Sharp, P.A.,Burge, C.B., 2008. Proliferating cells express mrnas with shortened 3' untranslated regions and fewer microrna target sites. Science 320, 1643-1647.

Singh, I., Lee, S.H., Sperling, A.S., Samur, M.K., Tai, Y.T., Fulciniti, M., Munshi, N.C., Mayr, C.,Leslie, C.S., 2018. Widespread intronic polyadenylation diversifies immune cell transcriptomes. Nat. Commun. 9, 1716.

Stroup, E.K.,Ji, Z., 2023. Deep learning of human polyadenylation sites at nucleotide resolution reveals molecular determinants of site usage and relevance in disease. Nat. Commun. 14, 7378.

Sun, R., Wei, T., Ding, D., Zhang, J., Chen, S., He, H.H., Wang, L.,Huang, H., 2022. Cyclin k down-regulation induces androgen receptor gene intronic polyadenylation, variant expression and parp inhibitor vulnerability in castration-resistant prostate cancer. Proc. Natl. Acad. Sci. U. S. A. 119, e2205509119.

Tang, P., Yang, Y., Li, G., Huang, L., Wen, M., Ruan, W., Guo, X., Zhang, C., Zuo, X., Luo, D., et al., 2022. Alternative polyadenylation by sequential activation of distal and proximal polya sites. Nat. Struct. Mol. Biol. 29, 21-31.

Tian, B.,Manley, J.L., 2017. Alternative polyadenylation of mrna precursors. Nat. Rev. Mol. Cell Biol. 18, 18-30.

Tian, B., Pan, Z.,Lee, J.Y., 2007. Widespread mrna polyadenylation events in introns indicate dynamic interplay between polyadenylation and splicing. Genome Res. 17, 156-165.

Van Houdt, W.J., Emmink, B.L., Pham, T.V., Piersma, S.R., Verheem, A., Vries, R.G., Fratantoni, S.A., Pronk, A., Clevers, H., Borel Rinkes, I.H., et al., 2011. Comparative proteomics of colon cancer stem cells and differentiated tumor cells identifies birc6 as a potential therapeutic target. Mol. Cell. Proteomics 10, M111.011353.

Woodford, M.R., Baker-Williams, A.J., Sager, R.A., Backe, S.J., Blanden, A.R., Hashmi, F., Kancherla, P., Gori, A., Loiselle, D.R., Castelli, M., et al., 2021. The tumor suppressor folliculin inhibits lactate dehydrogenase a and regulates the warburg effect. Nat. Struct. Mol. Biol. 28, 662-670.

Yang, G., Jiang, O., Ling, D., Jiang, X., Yuan, P., Zeng, G., Zhu, J., Tian, J., Weng, Y.,Wu, D., 2015. Microrna-522 reverses drug resistance of doxorubicin-induced ht29 colon cancer cell by targeting abcb5. Mol. Med. Rep. 12, 3930-3936.

Yi, D., Yilihamu, Y., Jiang, C., Wang, R., Lu, X., Sang, J.,Su, L., 2022. Mthfd1l knockdown diminished cells growth in papillary thyroid cancer. Tissue Cell 77, 101869.

Yu, G., Wang, L.G., Han, Y.,He, Q.Y., 2012. Clusterprofiler: an r package for comparing biological themes among gene clusters. OMICS 16, 284-287.

Zhang, H., Hu, J., Recce, M.,Tian, B., 2005. Polya_db: a database for mammalian mrna polyadenylation. Nucleic Acids Res. 33, D116-D120.

Zhang, Z., Lee, J.-H., Ruan, H., Ye, Y., Krakowiak, J., Hu, Q., Xiang, Y., Gong, J., Zhou, B., Wang, L., et al., 2019. Transcriptional landscape and clinical utility of enhancer rnas for erna-targeted therapy in cancer. Nat. Commun. 10, 4562.

Zhao, Z., Xu, Q., Wei, R., Huang, L., Wang, W., Wei, G.,Ni, T., 2021a. Comprehensive characterization of somatic variants associated with intronic polyadenylation in human cancers. Nucleic Acids Res. 49, 10369-10381.

Zhao, Z., Xu, Q., Wei, R., Wang, W., Ding, D., Yang, Y., Yao, J., Zhang, L., Hu, Y.Q., Wei, G., et al., 2021b. Cancer-associated dynamics and potential regulators of intronic polyadenylation revealed by ipafinder using standard rna-seq data. Genome Res. 31, 2095-2106.

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