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

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.

C8ORF59 regulates ribosome biogenesis to affect progression in lung adenocarcinoma

“…CX-5461, an RNA polymerase I inhibitor, can inhibit ribosome biogenesis, leading to growth, migration, and DNA damage induction in pancreatic ductal adenocarcinoma cells [21]. Silencing of the rRNA metabolism-associated cancer gene EXOSC8 reduces levels of nucleolar proteins and proliferation markers, as well as rRNA/DNA and global protein synthesis, inhibiting colorectal cancer cell proliferation [22]. These studies suggest that ribosome stress causes a series of disruptions in cellular biology.…”

Genomic hallmarks and therapeutic targets of ribosome biogenesis in cancer

“…For example, DDX17 was reported to serve as inflammasome sensor for SINE RNAs [ 68 ], and consistently down-regulated DDX17 may contribute to immune escape. Regarding the hallmarks of genomic alterations related to RiboSis, our multi-omic data revealed that the main genetic variation of RiboSis genes was CNV, suggesting that high-level amplification of RiboSis genes in tumors may be one of the main driving factors for hyperactive RiboSis [ 69 , 70 ]. Concerted copy number variation balances are important for ribosomal DNA [ 71 , 72 ].…”

ELOA promotes tumor growth and metastasis by activating RBP1 in gastric cancer

“…The subsequent steps were completed using the GT Vision III Detection System (GeneTech, China). H&E and IHC staining assays were carried out according to our previous methods 8,14,16 …”

“…Images were captured by a confocal microscope (ZEISS, LSM880, Germany). The detailed operation method can be found in our previous study 13,14 …”

“…The detailed operation method can be found in our previous study. 13,14 2.9 | Dual-luciferase reporter assay Transfections were performed using LipoFiter (HANBIO, China). Forty-eight hours after transfection, luciferase activities in the cells were assayed with a Dual-Luciferase Reporter Assay Kit (Vazyme) as we previously described.…”