Ribosome Biogenesis Alterations in Colorectal Cancer

Abstract

Many studies have focused on understanding the regulation and functions of aberrant protein synthesis in colorectal cancer (CRC), leaving the ribosome, its main effector, relatively underappreciated in CRC. The production of functional ribosomes is initiated in the nucleolus, requires coordinated ribosomal RNA (rRNA) processing and ribosomal protein (RP) assembly, and is frequently hyperactivated to support the needs in protein synthesis essential to withstand unremitting cancer cell growth. This elevated ribosome production in cancer cells includes a strong alteration of ribosome biogenesis homeostasis that represents one of the hallmarks of cancer cells. None of the ribosome production steps escape this cancer-specific dysregulation. This review summarizes the early and late steps of ribosome biogenesis dysregulations described in CRC cell lines, intestinal organoids, CRC stem cells and mouse models, and their possible clinical implications. We highlight how this cancer-related ribosome biogenesis, both at quantitative and qualitative levels, can lead to the synthesis of ribosomes favoring the translation of mRNAs encoding hyperproliferative and survival factors. We also discuss whether cancer-related ribosome biogenesis is a mere consequence of cancer progression or is a causal factor in CRC, and how altered ribosome biogenesis pathways can represent effective targets to kill CRC cells. The association between exacerbated CRC cell growth and alteration of specific steps of ribosome biogenesis is highlighted as a key driver of tumorigenesis, providing promising perspectives for the implementation of predictive biomarkers and the development of new therapeutic drugs.

A Transcriptomic Approach Reveals Selective Ribosomal Remodelling in the Tumour Versus the Stromal Compartment of Metastatic Colorectal Cancer

“…A distinctive feature of cancer cells is the constitutive activation of growth factor signalling pathways that alter the activity of transcription factors [33,34] responsible for the increased ribosome biogenesis due to the hyperactivation of RNA polymerases I and III [35,36]. Different reports have highlighted that ribosome biogenesis has a role in the initial phases of CRC tumour progression, mainly due to rRNA polymerase (or its cofactors) overexpression or mutation [37,38]. Another study [39] demonstrated that a germline mutation in RPS20, encoding a component of the small ribosomal subunit, increases the predisposition to develop a particular form of hereditary CRC named familial colorectal cancer type X (FCCX).…”

“…It is generally accepted that tumour cells, being characterised by enhanced growth, might also have increased ribosome production associated with altered biogenesis and nucleolar modifications (in either number, shape, or size) [37]. Moreover, the mounting evidence highlights the strong links between rRNA synthesis and rProteins with the development of human cancers [38].…”

Identification of Hub Genes in Different Stages of Colorectal Cancer through an Integrated Bioinformatics Approach

“…The top 40 hub genes detected from colorectal carcinoma (G3) datasets were found to be related to ribosome biogenesis in eukaryotes, rRNA processing, and pyrimidine and purine metabolism pathways. Previous studies have shown that the ribosome biogenesis pathway is altered in CRC, and the alterations lead to increased production of ribosomes linked to the initiation and progression of colorectal carcinogenesis [75]. Stedman et al (2015) showed that the dysfunction of ribosome biogenesis might also lead to p53-mediated apoptosis in some cancers [76].…”

Human RecQL4 as a Novel Molecular Target for Cancer Therapy

“…Some of the downregulated genes belong to the pathways of ribosome biogenesis, RNA transport, RNA degradation, and protein synthesis in endoplasmic reticulum. Ribosome biogenesis is hyperactivated in cancer cells to fulfill the increased demand of protein synthesis for sustaining an infinite growth potential [Slimane et al, 2020]. Downregulation of ribosome biogenesis in RecQL4-suppressed glioblastoma cells suggests that RecQL4 contributes to enhanced ribosome biogenesis.…”