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EXOSC8 promotes colorectal cancer tumorigenesis via regulating ribosome biogenesis-related processes

Oncogene volume 41, pages 5397–5410 (2022)Cite this article

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Abstract

Extensive protein synthesis is necessary for uncontrolled cancer cell proliferation, requiring hyperactive ribosome biogenesis. Our previous Pan-cancer study has identified EXOSC8 as a potential copy number variation (CNV)-driven rRNA metabolism-related oncogene in colorectal cancer (CRC). Herein, we further investigated proliferation-prompting functions and mechanisms of EXOSC8 in CRC by performing in silico analyses and wet-lab experiments. We uncovered that increased EXOSC8 expression and CNV levels are strongly associated with ribosome biogenesis-related factor levels in CRC, including ribosome proteins (RPs), eukaryotic translation initiation factors and RNA polymerase I/III. EXOSC8 silence decreases nucleolar protein and proliferation marker levels, as well as rRNA/DNA and global protein syntheses. Clinically, EXOSC8 is upregulated across human cancers, particularly CNV-driven upregulation in CRC was markedly associated with poor clinical outcomes. Mechanistically, EXOSC8 knockdown increased p53 levels in CRC, and the oncogenic proliferation phenotypes of EXOSC8 depended on p53 in vitro and in vivo. We discovered that EXOSC8 knockdown in CRC cells triggers ribosomal stress, nucleolar RPL5/11 being released into the nucleoplasm and “hijacking” Mdm2 to block its E3 ubiquitin ligase function, thus releasing and activating p53. Furthermore, our therapeutic experiments provided initial evidence that EXOSC8 might serve as a potential therapeutic target in CRC. Our findings revealed, for the first time, that the RNA exosome gene (EXOSC8) promotes CRC tumorigenesis by regulating cancer-related ribosome biogenesis in CRC. This study further extends our previous Pan-cancer study of the rRNA metabolism-related genes. The inhibition of EXOSC8 is a novel therapeutic strategy for the RPs-Mdm2-p53 ribosome biogenesis surveillance pathway in CRC.

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Fig. 1: EXOSC8 and ribosome biogenesis-related factors are co-expressed in CRC.
Fig. 2: EXOSC8 expression is required for ribosome biogenesis in CRC.
Fig. 3: EXOSC8 is upregulated in CRC.
Fig. 4: Upregulation of EXOSC8 predicts poor clinical outcomes for patients with CRC.
Fig. 5: EXOSC8 knockdown increases p53 in CRC.
Fig. 6: The oncogenic phenotypes of EXOSC8 depend on p53 in CRC.
Fig. 7: Inhibition of EXOSC8 triggers ribosomal stress in CRC.
Fig. 8: EXOSC8 might serve as a potential therapeutic target in CRC.

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Acknowledgements

We acknowledge the TCGA, GEO, CCLE and CPTAC projects. We would like to thank developers of each dataset, method and package used in this study. We thank the Affiliated Hospital of Jiangnan University for providing the CRC samples. We also thank the platforms of Medical Research Center (Wuxi School of Medicine, Jiangnan University). This work was supported by grants from the National Natural Science Foundation of China (82002550 and 82173063) and Wuxi Medical Key Discipline (ZDXK2021002).

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  1. These authors contributed equally: Kaisa Cui, Liang Gong.

Authors and Affiliations

  1. Wuxi Cancer Institute, Affiliated Hospital of Jiangnan University, Wuxi, Jiangsu, 214062, China

    Kaisa Cui, Han Zhang, Ying Chen, Zhicheng Gong, Yuanben Wang, Shengbai Sun, Yulin Cao & Zhaohui Huang

  2. Key Laboratory of Carbohydrate Chemistry & Biotechnology, Ministry of Education, School of Biotechnology, Jiangnan University, Wuxi, Jiangsu, 214122, China

    Liang Gong

  3. The Key Laboratory of Modern Toxicology of Ministry of Education, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing, Jiangsu, 211166, China

    Bingxin Liu

  4. Key Laboratory of Environment Medicine and Engineering of Ministry of Education, Department of Epidemiology and Health Statistics, School of Public Health, Southeast University, Nanjing, Jiangsu, 210009, China

    Jiuming Li

  5. State Key Laboratory of Cell Differentiation and Regulation, Henan International Joint Laboratory of Pulmonary Fibrosis, Outstanding Overseas Scientists Center for Pulmonary Fibrosis of Henan Province, College of Life Science, Institute of Biomedical Science, Henan Normal University, Xinxiang, Henan, 453000, China

    Yajun Li

  6. Department of Biochemistry, Molecular Cancer Research Center, School of Medicine, Shenzhen Campus of Sun Yat-sen University, Shenzhen, Guangdong, 518107, China

    Qiang Zhang

  7. Computer Vision Lab, Department of Electrical Engineering, California Institute of Technology, Pasadena, CA, 91125, USA

    Qilin Li

  8. Department of Surgical Oncology, Affiliated Hospital of Jiangnan University, Wuxi, Jiangsu, 214122, China

    Bojian Fei

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Contributions

KC initiated the entire study. KC designed and performed the bioinformatics analyses and visualization. BL and QL provided support for bioinformatics analysis. KC, LG, ZG, YL, QZ and ZH designed the wet-lab experiments. KC, LG, HZ, and YW performed molecular biology-related experiments. KC, LG, HZ, YiC, and YuC conducted in vitro and in vivo experiments on proliferation phenotypes. KC and LG performed the ribosome biogenesis-related experiments. KC, LG, HZ, ZG and JL conducted protein-related assays. BL, SS, YiC, YuC and BF performed CRC samples collective and information maintenance. LG and BL conducted IHC assays. LG performed therapeutic experiments. KC, LG, BL, ZG and ZH designed graphical abstract, and KC visualized it. KC and ZH supervised this project and mentored the participants. KC wrote the manuscript. KC, LG, ZG and ZH critically revised the manuscript. All authors discussed the results.

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Correspondence to Kaisa Cui or Zhaohui Huang.

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Cui, K., Gong, L., Zhang, H. et al. EXOSC8 promotes colorectal cancer tumorigenesis via regulating ribosome biogenesis-related processes. Oncogene 41, 5397–5410 (2022). https://doi.org/10.1038/s41388-022-02530-4

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