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.

Keywords: cancer; colorectal; human; rDNA; rRNA; ribosome; targeting; translation.

Figure 1

Regulation of early transcriptional steps of ribosome biogenesis in CRC. MYC is overexpressed in colorectal tumor cells, binds to rDNA sequences, and in cooperation with UBF and SL1 factors, leads to the hyperactivation of RNA pol I-mediated synthesis of the 47S rRNA precursor [84]. MYC, in cooperation with RPF2 and RRS1, activates RNA pol II-mediated transcription of genes coding for ribosomal assembly factors and RPs, as well as RNA pol III-mediated synthesis of 5S rRNA [57]. Overexpression of the three rRNA polymerases and the associated factors is frequent in CRC [80,81,82,83]. Together with RPF2 (protein ribosome production factor 2 homolog), RRS1 cooperates with POL III and drives 5S rRNA synthesis, while POL II activates ribosomal proteins and assembly factors mRNAs and snoRNAs synthesis.

Figure 2

Schematic representation of ribosome biogenesis factors upregulated in colorectal cancer cells and their known sites of regulation of pre-rRNA processing pathways. The production of mature 18S, 5.8S, and 28S result from the synthesis and processing of a single 47S rRNA precursor characterized by noncoding 5′ and 3′ external transcribed spacers (ETS) and internal transcribed spacers (ITS1 and ITS2). In colorectal cancer cells, overexpression of the 45S rRNA is a biomarker of poor prognosis [87]. RPL15 is involved in pre-rRNA processing at the internal transcribed spacer 1 (ITS1) site of the 47S pre-rRNA and is overexpressed in CRC [148]. RPL14 controls the processing of the 45S pre-rRNA and 12S rRNA and is highly expressed in CRC [140]. RPS6, RPS7, RPS 17, RPS20, and RPS24 are involved in the formation of the 18S rRNA and are overexpressed in CRC respectively, in References [132,139,141,142,150]. Pescadillo homolog 1 (PES1), block of proliferation (BOP1), and WD-repeat domain 12 protein (WDR12) are involved in the formation of the 12S rRNA and overexpressed in CRC respectively, in References [113,122,130]. PES1 is also involved with DDX21 and GNL3 in the processing of the 32S to the 28S rRNA and GNL3 is overexpressed in CRC [116]. RPL14, which is overexpressed in CRC [141], further activates the processing of the 12S rRNA to mature 5.8S. 18S pre-rRNA processing is activated by NIN1 (RPN12) binding protein 1 homolog (NOB1) in cooperation with “partner of NOB1” (PNO1) which is overexpressed in CRC [151]. 18S pre-rRNA processing is also activated by human U3 protein (UTP) 14a (hUTP14a), and is overexpressed and constitutes a marker of poor prognosis in CRC [152]. Base and nucleotide modifications are important modifications that control late steps of rRNA maturation. The human nucleolar enzyme NSUN5 catalyzes the C⁵ methylation of cytosine residue C₃₇₈₂ of the 28S rRNA (18S-m₅C3782) and is upregulated in CRC and associated with disease progression [153]. The C/D-Box small nucleolar RNA 16 (SNORD16) guides fibrillarin (FBL) to methylate the 2′O-ribose on the 18S-Am484 site and constitutes a molecular marker of CRC and a driver of colorectal tumorigenesis [154]. The ribosome biogenesis protein TSR3 induces the 1-methyl-3α-amino-α-carboxyl-propyl pseudouridine (m¹acp³Ψ) modification on uridine U1248 of the 18S rRNA and is overexpressed in CRC and associated with colorectal tumorigenesis [155].