Ribosome Biogenesis and Neoplastic Transformation

Ribosome Biogenesis in Cancer Development

Ribosome biogenesis is the process to form the translationally active 80S ribosome using 40S and 60S subunits. In eukaryotes, the assembly of rRNA, snoRNA, ribosomal proteins, and related proteins occurs in the nucleolus. Ribosome assembly and final maturation steps occur in the cytoplasm. It is well-known that the process of ribosome biogenesis is associated with human pathological conditions as well as the increased risk for cancer development. A variety of ribosomopathies result in the generation of altered ribosomes. Recent studies showed that nucleolar functional changes and regulation of ribosome biogenesis rate play important roles in neoplastic transformation.

Fig. 1 The relationship between ribosome biogenesis rate and the level of p53 stabilization.¹

• Ribosome Biogenesis Rate and Cancer Development

In many human cells, nucleolar hypertrophy leading to increased rates of ribosome biosynthesis has been found. Dysfunctions of p53 and pRb showed markedly enlarged nucleoli in tumor cells, ultimately resulting in uncontrolled cell proliferation and upregulation of rRNA transcriptional activity. This phenomenon often occurs in human hepatocytes with chronic inflammatory disease, colonic mucosal epithelial cells with chronic ulcerative disease, as well as pancreatic acinar cells with chronic pancreatitis. In conclusion, an increase in the rate of ribosome biosynthesis leads to a significantly increased risk of cancer.

• Qualitative Alterations in Ribosome Biogenesis and Cancer

Qualitative alterations in ribosome biogenesis have emerged as an important mechanism by which altered ribosome biogenesis contributes to cancer. Altered ribosomes can translate differentially specific mRNAs that ultimately increase the expression of certain oncogenes or decrease the expression of certain tumor suppressors. In addition, decreased rRNA production or deficiency of specific ribosomal proteins induces activation of the p53 response that increases the risk of cancer development and progression.

• Ribosome Biogenesis and Cell Cycle Regulation

Studies have shown that impaired ribosome biosynthesis induces checkpoint control that blocks cell proliferation and interferes with cell cycle regulation. There are both p53-dependent and p53-independent mechanisms linking ribosome biogenesis and cell cycle regulation. The p53-dependent mechanism of action is that p21-mediated inhibition of pRb phosphorylation blocks the G1/S phase transition and impedes cell proliferation. The p53-independent mechanism is that silencing the POLR1A gene downregulates the expression of the transcription factor E2F-1, ultimately inhibiting rRNA synthesis and cell cycle progression

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Reference

1. Penzo, Marianna, et al. "The ribosome biogenesis—cancer connection." Cells 8.1 (2019): 55.