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Pan-cancer pseudogene RNA analysis reveals a regulatory network promoting cancer cell proliferation

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Abstract

Pseudogenes have long been thought to be nonfunctional due to their lack of protein-coding ability, compared to protein-coding genes (PCG). Actually, pseudogenes can transcribe functional long non-coding RNAs (lncRNAs) involved in cancer development and progression. These lncRNAs may regulate mRNA levels as competing endogenous RNAs (ceRNAs). However, a systematic pan-cancer analysis of pseudogene ceRNA networks is still lacking. Here, we curated 9455 pseudogenes and constructed ceRNA networks for 14 cancer types. We discovered that pseudogenes in ceRNA networks were the most cancer type-specific and that ~ 20% cePCGs were cancer hallmark genes, supporting the close relationship between pseudogenes and cancer. Notably, in breast cancer (BRCA), we found that the ceRNA subnetwork of ZNF252P/AL390726.5 (pseudogenes)-miRNAs-ESR1 may enhance the proto-oncogene MYC and we experimentally validated oncogenic effects of the two pseudogenes. Moreover, pseudogene-based subtyping of BRCA tumors revealed a new subtype featured by immunoglobulin pseudogenes. Collectively, our findings could pave the way for more pseudogene research in cancer. We provided our results in a user-friendly database, cePseudo, available at http://bioinfo-sysu.com/cePseudo2.

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Data availability

GTEx RNA-seq sequencing reads files were downloaded from dbGaP (phs000424.v8.p2). TCGA RNA-seq BAM files were downloaded from GDC (https://portal.gdc.cancer.gov). Expression levels of PCGs (HTSeq-FPKM and HTSeq-Counts) and miRNAs (mirbase21.isoforms.quantification.txt) and clinical information were downloaded from the UCSC Xena database (https://xenabrowser.net). CPTAC proteomics data were available at https://proteomics.cancer.gov/programs/cptac.

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Acknowledgements

The research has been supported by the Integrated Project of Major Research Plan of National Natural Science Foundation of China (NSFC) (92249303) and Guangdong Basic and Applied Basic Research Foundation (2021A1515110972). The results shown here are in whole or in part based upon data generated by the TCGA or CPTAC Research Network.

Funding

Integrated Project of Major Research Plan of National Natural Science Foundation of China, 92249303, Yuanyan Xiong; Basic and Applied Basic Research Foundation of Guangdong Province, 2021A1515110972, Mengbiao Guo.

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  1. Mengbiao Guo, Jingkai Zhang, Qiaoling Liang and Jianxi Zhu have contributed equally.

Authors and Affiliations

  1. Institute of Healthy Aging Research, School of Life Sciences, Key Laboratory of Gene Engineering of the Ministry of Education, Sun Yat-sen University, Guangzhou, 510006, China

    Mengbiao Guo, Jingkai Zhang, Qiaoling Liang, Jianxi Zhu, Zhengwen Fang, Zhou Songyang & Yuanyan Xiong

  2. Clinical Research Center, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, 518107, China

    Qi Wang

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  1. Mengbiao Guo
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  2. Jingkai Zhang
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  5. Qi Wang
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Contributions

YYX and MBG conceived the project. QLL, MBG, and JKZ analyzed the data and interpreted the results. JXZ, QW, MHX, and ZWF performed experimental validation. MBG wrote the manuscript. MBG and JKZ revised the manuscript. YYX, MBG, QW, and ZSY reviewed the manuscript. All authors approved the final manuscript.

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Correspondence to Zhou Songyang or Yuanyan Xiong.

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Guo, M., Zhang, J., Liang, Q. et al. Pan-cancer pseudogene RNA analysis reveals a regulatory network promoting cancer cell proliferation. GENOME INSTAB. DIS. 4, 85–97 (2023). https://doi.org/10.1007/s42764-023-00097-2

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