Cui Kaisa, Gong Liang, Zhang Han, Chen Ying, Liu Bingxin, Gong Zhicheng, Li Jiuming, Wang Yuanben, Sun Shengbai, Li Yajun, Zhang Qiang, Cao Yulin, Li Qilin, Fei Bojian, Huang Zhaohui
Wuxi Cancer Institute, Affiliated Hospital of Jiangnan University, Wuxi, Jiangsu, 214062, China.
Key Laboratory of Carbohydrate Chemistry & Biotechnology, Ministry of Education, School of Biotechnology, Jiangnan University, Wuxi, Jiangsu, 214122, China.
Oncogene. 2022 Dec;41(50):5397-5410. doi: 10.1038/s41388-022-02530-4. Epub 2022 Nov 8.
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.
广泛的蛋白质合成对于癌细胞的无节制增殖是必需的，这需要核糖体生物合成的过度活跃。我们之前的泛癌研究已将EXOSC8鉴定为结直肠癌（CRC）中一种潜在的拷贝数变异（CNV）驱动的与rRNA代谢相关的癌基因。在此，我们通过进行计算机分析和湿实验室实验，进一步研究了EXOSC8在CRC中的促增殖功能及机制。我们发现，CRC中EXOSC8表达和CNV水平的升高与核糖体生物合成相关因子水平密切相关，包括核糖体蛋白（RPs）、真核翻译起始因子以及RNA聚合酶I/III。EXOSC8沉默会降低核仁蛋白和增殖标志物水平，以及rRNA/DNA和整体蛋白质合成。临床上，EXOSC8在人类癌症中均上调，尤其是在CRC中CNV驱动的上调与不良临床结局显著相关。机制上，EXOSC8敲低会增加CRC中的p53水平，并且EXOSC8的致癌增殖表型在体外和体内均依赖于p53。我们发现，CRC细胞中EXOSC8敲低会引发核糖体应激，核仁中的RPL5/11释放到核质中并“劫持”Mdm2以阻断其E3泛素连接酶功能，从而释放并激活p53。此外，我们的治疗实验提供了初步证据，表明EXOSC8可能是CRC中的一个潜在治疗靶点。我们的研究首次揭示，RNA外切体基因（EXOSC8）通过调节CRC中与癌症相关的核糖体生物合成来促进CRC肿瘤发生。本研究进一步扩展了我们之前对与rRNA代谢相关基因的泛癌研究。抑制EXOSC8是针对CRC中RPs - Mdm2 - p53核糖体生物合成监测途径的一种新型治疗策略。
