Unraveling the Mechanisms of Ribosome Biogenesis in Cancer

Abstract

Ribosome biogenesis is a fundamental process to cellular function that generates the ribosomes required for protein synthesis. This pathway involves the transcription, processing, maturation, and assembly of ribosomal RNA that ultimately leads to the formation of the ribosomal subunits. Because it is complex, resource-intensive, and energetically demanding, it is normally tightly regulated. In cancer cells, however, oncogenic signaling increases ribosome biogenesis to support rapid cell growth. In this study, we found that although oncogene activation significantly increased nucleolar transcriptional activity, nucleolar rRNA outflux remained largely similar between oncogene-hyperactive and normal states, suggesting that increased transcription alone did not explain how efficiently material progressed through the pathway. This raised the question of whether downstream processing and maturation steps were able to keep pace under oncogenic stress. By comparing newly synthesized pre-rRNA with newly produced ribosomes, we found that oncogene activation increases transcriptional input without producing a proportional increase in mature ribosome output, indicating reduced ribosome biogenesis efficiency. Pulse-chase sequencing following rRNA processing over time revealed that malignant cells progress more slowly specifically through late-stage processing steps. Perturbing factors involved in these late maturation stages selectively reduced ribosome biogenesis in oncogene-hyperactive cells, both in vitro and in vivo. These findings suggest that elevated ribosome biogenesis in cancer is limited by downstream processing capacity, revealing late-stage bottlenecks as selective vulnerabilities that can potentially be utilized as targets for future therapeutics.