The impact of ribosome biogenesis in cancer: from proliferation to metastasis

Abstract

The dysregulation of ribosome biogenesis is a hallmark of cancer, facilitating the adaptation to altered translational demands essential for various aspects of tumor progression. This review explores the intricate interplay between ribosome biogenesis and cancer development, highlighting dynamic regulation orchestrated by key oncogenic signaling pathways. Recent studies reveal the multifaceted roles of ribosomes, extending beyond protein factories to include regulatory functions in mRNA translation. Dysregulated ribosome biogenesis not only hampers precise control of global protein production and proliferation but also influences processes such as the maintenance of stem cell-like properties and epithelial-mesenchymal transition, contributing to cancer progression. Interference with ribosome biogenesis, notably through RNA Pol I inhibition, elicits a stress response marked by nucleolar integrity loss, and subsequent G1-cell cycle arrest or cell death. These findings suggest that cancer cells may rely on heightened RNA Pol I transcription, rendering ribosomal RNA synthesis a potential therapeutic vulnerability. The review further explores targeting ribosome biogenesis vulnerabilities as a promising strategy to disrupt global ribosome production, presenting therapeutic opportunities for cancer treatment.

Graphical Abstract

Figure 1.

The different steps of ribosome biogenesis in the nucleolus. The process of ribosome biogenesis involves transcription by all three RNA polymerases. Initially, Pol I transcribes the 47S pre-rRNA in the nucleolus. This 47S pre-rRNA undergoes a series of cleavage and modification events orchestrated by various processing factors, resulting in the formation of the 18S, 5.8S and 28S rRNAs. These steps occur sequentially in distinct nucleolar subcompartments. Meanwhile, Pol III in the nucleoplasm transcribes the 5S rRNA, which complexes with uL18 and uL5 to form the 5S RNP, joining the pre-60S ribosomal subunit in the GC. RNA Pol II, also in the nucleoplasm, transcribes both snoRNAs and mRNAs encoding RPs and processing factors. These mRNA transcripts are translated in the cytoplasm, and their protein products are subsequently transported back to the nucleolus to participate in the assembly of the pre-40S and pre-60S subunits. Additionally, tRNAs, essential for translation, are transcribed by RNA Pol III. Throughout ribosome maturation, spanning various nucleolar subcompartments and nucleoplasm, the final maturation steps occur in the cytoplasm. This is also the site where protein synthesis takes place. Created with BioRender.com.

Figure 2.

Signaling pathways regulate rRNA transcription by targeting RNA Pol I pre-initiation complex (PIC). A variety of oncogenes (green) and tumor suppressor proteins (red) regulate 47S rRNA transcription via activation or inhibition of the PIC of Pol I.

Figure 3.

The interplay between cell proliferation, rDNA transcription and protein synthesis during EMT and MET. During EMT, along with cell cycle arrest and reduction in DNA synthesis, there is a surge in rRNA production coupled with the enlargement of nucleoli, indicating an activation of ribosome biogenesis. The elevated ribosome level is essential to meet the high demand for protein synthesis, facilitating the establishment of a new proteome during and after the transition. Similarly, this trend is mirrored in the reversal process, MET, underlining the critical role of increased ribosome biogenesis and protein synthesis during these transition processes. Additionally, in migrating mesenchymal cells, there's a specific localization of RP-mRNAs translation within cell protrusions, contributing to an overall increase in ribosome biogenesis required for the cell invasion process. Created with BioRender.com.