Abstract
Dysfunctions in ribosome biogenesis cause developmental defects and increased cancer susceptibility; however, the connection between ribosome assembly and tumorigenesis remains unestablished. Here we show that hCINAP (also named AK6) is required for human 18S rRNA processing and 40S subunit assembly. Homozygous CINAP−/− mice show embryonic lethality. The heterozygotes are viable and show defects in 18S rRNA processing, whereas no delayed cell growth is observed. However, during rapid growth, CINAP haploinsufficiency impairs protein synthesis. Consistently, hCINAP depletion in fast-growing cancer cells inhibits ribosome assembly and abolishes tumorigenesis. These data demonstrate that hCINAP reduction is a specific rate-limiting controller during rapid growth. Notably, hCINAP is highly expressed in cancers and correlated with a worse prognosis. Genome-wide polysome profiling shows that hCINAP selectively modulates cancer-associated translatome to promote malignancy. Our results connect the role of hCINAP in ribosome assembly with tumorigenesis. Modulation of hCINAP expression may be a promising target for cancer therapy.
Highlights
Dysfunctions in ribosome biogenesis cause developmental defects and increased cancer susceptibility; the connection between ribosome assembly and tumorigenesis remains unestablished
We show that hCINAP is required for human 18S rRNA processing. hCINAP is highly expressed in cancers and promotes cancer cell growth through selectively upregulates the translation of cancer-associated genes
MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assays showed that depletion of hCINAP significantly inhibited cancer cell growth (Fig. 2l). These results demonstrate that the defects of 18S rRNA processing and protein synthesis by hCINAP depletion are strikingly amplified in cancer cells and limit cancer cell proliferation
Summary
Dysfunctions in ribosome biogenesis cause developmental defects and increased cancer susceptibility; the connection between ribosome assembly and tumorigenesis remains unestablished. HCINAP depletion in fast-growing cancer cells inhibits ribosome assembly and abolishes tumorigenesis These data demonstrate that hCINAP reduction is a specific rate-limiting controller during rapid growth. P53 inhibits RNA polymerase I transcription by hindering the formation of a complex necessary for the recruitment of RNA polymerase I to the rRNA gene promoter[1,5,15] These findings raise the possibility that oncogenes and tumour suppressors may affect cancer progression partly by controlling ribosome production[16]. As ribosome biogenesis are tightly correlated with translational regulation, increased cancer susceptibility associated with altered ribosomal activity may be due to an increased protein synthesis rate and selection of specific cancer-associated messenger RNAs for translation[10,17,18], as in the case of congenital dyskeratosis[19]. Reduced hCINAP abundance impairs tumorigenesis, suggesting that hCINAP could serve as a diagnostic marker and chemotherapeutic target
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