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3′untranslated regions of tumor suppressor genes evolved specific features to favor cancer resistance

Oncogene volume 41, pages 3278–3288 (2022)Cite this article

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Abstract

Cancer-related genes have evolved specific genetic and genomic features to favor tumor suppression. Previously we reported that tumor suppressor genes (TSGs) acquired high promoter CpG dinucleotide frequencies during evolution to maintain high expression in normal tissues and resist cancer-specific downregulation. In this study, we investigated whether 3′untranslated regions (3′UTRs) of TSGs have evolved specific features to carry out similar functions. We found that 3′UTRs of TSGs, especially those involved in multiple histological types and pediatric cancers, are longer than those of non-cancer genes. 3′UTRs of TSGs also exhibit higher density of binding sites for RNA-binding proteins (RBPs), particularly those having high affinities to C-rich motifs. Both longer 3′UTR length and RBP binding sites enrichment are correlated with higher gene expression in normal tissues across tissue types. Moreover, both features together with the correlated N6-methyladenosine modification and the extent of protein-protein interactions are positively associated with the ability of TSGs to resist cancer-specific downregulation. These results were successfully validated with independent datasets. Collectively, these findings indicate that TSGs have evolved longer 3′UTR with increased propensity to RBP binding, N6-methyladenosine modification and protein-protein interactions for optimizing their tumor-suppressing functions.

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Fig. 1: TSGs have longer 3′UTR than non-cancer genes.
Fig. 2: 3′UTR features associated with gene expression.
Fig. 3: Comparison of the association between 3′UTR features and gene expression level across different gene age classes.
Fig. 4: TSGs acquired longer 3′UTR to withstand downregulation in cancer.
Fig. 5: Comparison of the influence of 3′UTR-related features on TSG downregulation in cancer types with different extent of TSG involvement.
Fig. 6: Results validation with independent datasets.

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Data availability

Processed gene expression data were obtained from the firebrowse database (http://firebrowse.org/), GTEx Portal (https://gtexportal.org) and Gene Expression Omnibus (GEO, https://www.ncbi.nlm.nih.gov/geo/).

Code availability

Computer codes used in this study are available at the GitHub page: https://github.com/Hd0909/Evolution-of-3UTR.

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Acknowledgements

The results shown here are in part based upon data generated by TCGA Research Network: https://www.cancer.gov/tcga.

Funding

This work was supported by the Shenzhen Science and Technology Programme (JCYJ20180508161604382 awarded to WKKW), Shenzhen Science and Technology Innovation Commission, and National Natural Science Foundation of China (NSFC; 82103245).

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  1. These authors contributed equally: Dan Huang, Xiansong Wang

Authors and Affiliations

  1. Department of Anaesthesia and Intensive Care and Peter Hung Pain Research Institute, The Chinese University of Hong Kong, Hong Kong, People’s Republic of China

    Dan Huang, Xiansong Wang, Ziheng Huang, Yingzhi Liu, Xiaodong Liu, Tony Gin, Lin Zhang, Matthew Tak Vai Chan, Huarong Chen & William Ka Kei Wu

  2. CUHK Shenzhen Research Institute, Shenzhen, Guangdong, People’s Republic of China

    Dan Huang, Xiansong Wang, Ziheng Huang, Yingzhi Liu, Xiaodong Liu, Sunny Hei Wong, Jun Yu, Lin Zhang, Matthew Tak Vai Chan, Huarong Chen & William Ka Kei Wu

  3. Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong, People’s Republic of China

    Sunny Hei Wong, Jun Yu & Lin Zhang

  4. Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong, People’s Republic of China

    Sunny Hei Wong, Jun Yu, Lin Zhang, Matthew Tak Vai Chan, Huarong Chen & William Ka Kei Wu

  5. State Key Laboratory of Digestive Diseases, The Chinese University of Hong Kong, Hong Kong, People’s Republic of China

    Sunny Hei Wong, Jun Yu, Lin Zhang, Huarong Chen & William Ka Kei Wu

  6. Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore, Singapore

    Sunny Hei Wong

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Contributions

WKKW, HC and MTVC conceived and supervised the study. DH and XW performed bioinformatic analysis. DH, HC and WKKW wrote the manuscript. The remaining authors analyzed the data and assisted in editing. All authors approved the final version to be published and agree to be accountable for all aspects of the work.

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Correspondence to Matthew Tak Vai Chan, Huarong Chen or William Ka Kei Wu.

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Huang, D., Wang, X., Huang, Z. et al. 3′untranslated regions of tumor suppressor genes evolved specific features to favor cancer resistance. Oncogene 41, 3278–3288 (2022). https://doi.org/10.1038/s41388-022-02343-5

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