Ribosome Biogenesis and Function in Cancer: From Mechanisms to Therapy

Abstract

Ribosome biogenesis is a highly coordinated, multi-step process that assembles the ribosomal machinery responsible for translating mRNAs into proteins. It begins with the rate-limiting step of RNA polymerase I (Pol I) transcription of the 47S ribosomal RNA (rRNA) genes within a specialised nucleolar region in the nucleus, followed by rRNA processing, modification, and assembly with ribosomal proteins and the 5S rRNA produced by Pol III. The ribosomal subunits are then exported to the cytoplasm to form functional ribosomes. This process is tightly regulated by the PI3K/RAS/MYC oncogenic network, which is frequently deregulated in many cancers. As a result, ribosome synthesis, mRNA translation, and protein synthesis rates are increased. Growing evidence supports the notion that dysregulation of ribosome biogenesis and mRNA translation plays a pivotal role in the pathogenesis of cancer, positioning the ribosome as a promising therapeutic target. In this review, we summarise current understanding of dysregulated ribosome biogenesis and function in cancer, evaluate the clinical development of ribosome targeting therapies, and explore emerging targets for therapeutic intervention in this rapidly evolving field.

Keywords: cancer therapy; mRNA translation; nucleolus; pol I transcription; ribosome biogenesis.

Figure 1

A canonical rRNA gene unit contains the 47S pre-rRNA coding region, embedded with 18S, 5.8S, and 28S rRNA sequences separated by ETS and ITS, and the intergenic spacer (IGS). The IGS consists of the core promoter and UCE elements, enhancers, and transcription termination site. (Created in https://BioRender.com).

Figure 2

Ribosome biogenesis begins with the rate-limiting step of rRNA gene transcription by Pol I. 47S pre-rRNA transcripts are cleaved, modified, and processed with RPs and RBFs into pre-40S and -60S ribosomes. XPO1 mediates the export of pre-ribosomal subunits into the cytoplasm, where they undergo further modifications and interact with translation factors to form mature 80S ribosomes competent for protein synthesis. (Created in https://BioRender.com).

Figure 3

The nucleolus is a membrane-less organelle within the nucleus, where its formation is underpinned by rRNA gene transcription. The fibrillar centre (FC) contains inactive rRNA genes and unengaged Pol I transcription factors and is surrounded by the dense fibrillar centre (DFC) within the granular component (GC). Pol I transcription occurs at the boundary of the FC and DFC. Pre-rRNA processing, cleavage, and modification occur in the DFC. Assembly of pre-ribosomal subunits takes place in the GC. (Created in https://BioRender.com).

Figure 4

Oncogenic pathways that drive ribosome biogenesis and mRNA translation. Master regulator MYC induces Pol I, II, and III activities, allowing increased production of rRNAs, RPs, RBFs, and other RNA species required for ribosome synthesis and protein production. PI3K/Akt and Ras–ERK pathways, via multiple downstream factors, activate mTORC1, stimulating mRNA translation. (Created in https://BioRender.com).

Figure 5

Current landscape of ribosome-targeting strategies in cancer therapy. Chemotherapeutics, including alkylating-like platinum compounds, DNA intercalators, antimetabolites, and topoisomerase inhibitors, inhibit ribosome biogenesis at the rRNA transcription and processing stages. Several Pol I inhibitors (BMH-21, CX-5461, and PMR-116) have been developed to target rRNA gene transcription. Translation initiation is inhibited through direct inhibition of the translational machinery and inhibition of upstream signalling pathways. Omacetaxine blocks translation elongation by preventing the formation of peptide bonds. SINE compound Selinexor (KPT-330) limits nuclear export of various nucleic acids and proteins involved in protein synthesis. (Created in https://BioRender.com).