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

Cui, Kaisa and Gong, Liang and Zhang, Han and Chen, Ying and Liu, Bingxin and Gong, Zhicheng and Li, Jiuming and Wang, Yuanben and Sun, Shengbai and Li, Yajun and Zhang, Qiang and Cao, Yulin and Li, Qilin and Fei, Bojian and Huang, Zhaohui (2022) EXOSC8 promotes colorectal cancer tumorigenesis via regulating ribosome biogenesis-related processes. Oncogene, 41 (50). pp. 5397-5410. ISSN 0950-9232. doi:10.1038/s41388-022-02530-4.

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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.

Item Type:Article
Related URLs:
URLURL TypeDescription ReadCube access
Cui, Kaisa0000-0001-7255-2689
Gong, Liang0000-0002-6069-7650
Sun, Shengbai0000-0002-5842-6464
Zhang, Qiang0000-0002-8376-131X
Li, Qilin0000-0002-7191-8965
Fei, Bojian0000-0002-3672-0216
Huang, Zhaohui0000-0002-0117-9976
Additional Information: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).
Funding AgencyGrant Number
National Natural Science Foundation of China82173063
National Natural Science Foundation of China82002550
Wuxi Medical Key DisciplineZDXK2021002
Issue or Number:50
Record Number:CaltechAUTHORS:20221122-564647900.23
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Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:118006
Deposited By: Research Services Depository
Deposited On:07 Dec 2022 18:34
Last Modified:25 Jan 2023 23:00

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