How Cancer Exploits Ribosomal RNA Biogenesis: A Journey beyond the Boundaries of rRNA Transcription

Gaviraghi, Marco; Vivori, Claudia; Tonon, Giovanni

doi:10.3390/cells8091098

Cited by 30 publications

(35 citation statements)

References 131 publications

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“…Cancer cells are characterized by constitutive activation of growth signals which alter the activity of major cell cycle regulating transcription factors [49,50], and the increase in ribosome biogenesis in cancer cells has been extensively linked to the sustained activation of RNA polymerases I and III by these cell cycle transcription factors [51,52]. However, in addition to regulating rDNA gene transcription, some oncogenic transcription factors have been shown to coordinate the overall ribosome biogenesis process.…”

Section: Regulation Of Ribosome Biogenesis By Oncogenes and Tumor Supmentioning

confidence: 99%

“…Additional oncogenes such as mTOR, PI3K, and Akt were also shown to activate rRNA synthesis partly by directly interacting with the formation of the rDNA preinitiation complex (PIC) [63]. Conversely, tumor suppressors including TP53, PTEN, and RB are very potent ribosome biogenesis suppressors [51,52], regulating various levels from rDNA transcription and processing to RPs and accessory factor expression [64].…”

Section: Regulation Of Ribosome Biogenesis By Oncogenes and Tumor Supmentioning

confidence: 99%

“…Although it is well documented that ribosome biogenesis can be controlled by growth factor receptors through MAPK/RAS/signaling [52,91] and that constitutive activation of KRAS represents a major determinant of some CRC subtypes, only few studies have explored the contribution of the oncogenic RAS pathway in ribosome biogenesis-mediated colorectal tumorigenesis. Human colorectal cancer cell lines with constitutive KRAS activation display a gene signature enriched in ribosome biogenesis and translation factors [92].…”

Section: Myc and Ras Regulations Of Ribosome Biogenesis In Crcmentioning

confidence: 99%

“…The quantitative variations in RP expression levels described in CRC were mainly associated with extra-ribosomal effects leading to what is recognized as the nucleolar or ribosomal stress [132]. The nucleolar stress is caused by genetic mutations or altered expression levels of RP which are consequently not incorporated in ribosomes but bind to the E3 ubiquitin ligase, MDM2, thereby inducing stabilization of p53 and apoptosis activation [52,133]. Diseases associated with RP gene mutations are known as ribosomopathies and are often linked to cancer predisposition [46,68,94,131,[134][135][136][137].…”

Section: Regulation Of Ribosome Biogenesis By Ribosomal Proteins In Crcmentioning

confidence: 99%

“…The rationale for targeting ribosome biogenesis in cancer is based on experimental and clinical evidence showing that tumorigenesis is associated with quantitative increases in ribosome production and/or production of qualitatively-altered ribosome species [44,45,47,48,52,[170][171][172][173]. These characteristics have formed the basis for the development of new drugs that disrupt the activation of rRNA synthesis by directly targeting the formation and activity of the RNA pol I transcriptional complex on rDNA [51,[174][175][176].…”

Section: Targeting Ribosome Rna Synthesis In Colorectal Cancermentioning

confidence: 99%

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Ribosome Biogenesis Alterations in Colorectal Cancer

Slimane

Marcel

Fenouil

et al. 2020

Cells

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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.

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Section: Regulation Of Ribosome Biogenesis By Oncogenes and Tumor Supmentioning

confidence: 99%

Section: Regulation Of Ribosome Biogenesis By Oncogenes and Tumor Supmentioning

confidence: 99%

Section: Myc and Ras Regulations Of Ribosome Biogenesis In Crcmentioning

confidence: 99%

Section: Regulation Of Ribosome Biogenesis By Ribosomal Proteins In Crcmentioning

confidence: 99%

Section: Targeting Ribosome Rna Synthesis In Colorectal Cancermentioning

confidence: 99%

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Ribosome Biogenesis Alterations in Colorectal Cancer

Slimane

Marcel

Fenouil

et al. 2020

Cells

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Identification of three small nucleolar RNAs (snoRNAs) as potential prognostic markers in diffuse large B‐cell lymphoma

Huang

Xie

et al. 2022

Cancer Medicine

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Background Diffuse large B‐cell lymphoma (DLBCL) is a non‐Hodgkin lymphoma with high mortality rates. Small nucleolar RNAs (snoRNAs) are tumor‐specific biological markers, but there are few studies on the role of snoRNAs in DLBCL. Materials and Methods Survival‐related snoRNAs were selected to construct a specific snoRNA‐based signature via computational analyses (Cox regression and independent prognostic analyses) to predict the prognosis of DLBCL patients. To assist in clinical applications, a nomogram was built by combining the risk model and other independent prognostic factors. Pathway analysis, gene ontology analysis, transcription factor enrichment, protein–protein interactions, and single nucleotide variant analysis were used to explore the potential biological mechanisms of co‐expressed genes. Results Twelve prognosis‐correlated snoRNAs were selected from the DLBCL patient cohort of microarray profiles, and a three‐snoRNA signature consisting of SNORD1A, SNORA60, and SNORA66 was constructed. DLBCL patients could be divided into high‐risk and low‐risk cohorts using the risk model, and the high‐risk group and activated B cell‐like (ABC) type DLBCL were linked with disappointing survival. In addition, SNORD1A co‐expressed genes were inseparably linked to the biological functions of the ribosome and mitochondria. Potential transcriptional regulatory networks have also been identified. MYC and RPL10A were the most mutated SNORD1A co‐expressed genes in DLBCL. Conclusion Put together, our findings explored the potential biological effects of snoRNAs in DLBCL, and provided a new predictor for DLBCL prediction.

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TTF1 control of LncRNA synthesis delineates a tumor suppressor pathway directly regulating the ribosomal RNA genes

Sibai,

Tremblay,

Lessard

et al. 2024

Journal Cellular Physiology

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The tumor suppressor p14/19ARF regulates ribosomal RNA (rRNA) synthesis by controlling the nucleolar localization of Transcription Termination Factor 1 (TTF1). However, the role played by TTF1 in regulating the rRNA genes and in potentially controlling growth has remained unclear. We now show that TTF1 expression regulates cell growth by determining the cellular complement of ribosomes. Unexpectedly, it achieves this by acting as a “roadblock” to synthesis of the noncoding LncRNA and pRNA that we show are generated from the “Spacer Promoter” duplications present upstream of the 47S pre‐rRNA promoter on the mouse and human ribosomal RNA genes. Unexpectedly, the endogenous generation of these noncoding RNAs does not induce CpG methylation or gene silencing. Rather, it acts in cis to suppress 47S preinitiation complex formation and hence de novo pre‐rRNA synthesis by a mechanism reminiscent of promoter interference or occlusion. Taken together, our data delineate a pathway from p19ARF to cell growth suppression via the regulation of ribosome biogenesis by noncoding RNAs and validate a key cellular growth law in mammalian cells.

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How Cancer Exploits Ribosomal RNA Biogenesis: A Journey beyond the Boundaries of rRNA Transcription

Cited by 30 publications

References 131 publications

Ribosome Biogenesis Alterations in Colorectal Cancer

Ribosome Biogenesis Alterations in Colorectal Cancer

Identification of three small nucleolar RNAs (snoRNAs) as potential prognostic markers in diffuse large B‐cell lymphoma

TTF1 control of LncRNA synthesis delineates a tumor suppressor pathway directly regulating the ribosomal RNA genes

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