A single H/ACA small nucleolar RNA mediates tumor suppression downstream of oncogenic RAS DOI Creative Commons
Mary McMahon, Adrian Contreras, Mikael Holm

et al.

eLife, Journal Year: 2019, Volume and Issue: 8

Published: Sept. 3, 2019

Small nucleolar RNAs (snoRNAs) are a diverse group of non-coding that direct chemical modifications at specific residues on other RNA molecules, primarily ribosomal (rRNA). SnoRNAs altered in several cancers; however, their role cell homeostasis as well cellular transformation remains poorly explored. Here, we show subsets snoRNAs differentially regulated during the earliest response to oncogenic RASG12V expression. We describe novel function for one H/ACA snoRNA, SNORA24, which guides two pseudouridine within small subunit, RAS-induced senescence vivo. find mouse models, loss Snora24 cooperates with promote development liver cancer closely resembles human steatohepatitic hepatocellular carcinoma (HCC). From clinical perspective, further HCCs low SNORA24 expression display increased lipid content and associated poor patient survival. next asked whether ribosomes lacking SNORA24-guided 18S rRNA have alterations biophysical properties. Single-molecule Fluorescence Resonance Energy Transfer (FRET) analyses revealed these exhibit perturbations aminoacyl-transfer (aa-tRNA) selection pre-translocation ribosome complex dynamics. Furthermore, HCC cells translational miscoding stop codon readthrough frequencies. These findings highlight safeguarding against insult demonstrate functional link between by RAS properties cancer.

Language: Английский

A Photocaged, Water-Oxidizing, and Nucleolus-Targeted Pt(IV) Complex with a Distinct Anticancer Mechanism DOI
Zhiqin Deng, Na Wang, Yingying Liu

et al.

Journal of the American Chemical Society, Journal Year: 2020, Volume and Issue: 142(17), P. 7803 - 7812

Published: March 27, 2020

Targeted anticancer prodrugs that can be controllably activated are highly desired for personalized precision medicine in cancer therapy. Such with unique action modes also promising to overcome drug resistance. Herein, we report coumaplatin, an oxaliplatin-based and photocaged Pt(IV) prodrug, realize nuclear accumulation along "on-demand" activation. This prodrug is based on a complex efficiently photoactivated via water oxidation without the requirement of reducing agent. Coumaplatin accumulates very nucleoli, upon photoactivation, this exhibits level photocytotoxicity up 2 orders magnitude higher than oxaliplatin. Unexpectedly, presents strikingly enhanced tumor penetration ability utilizes distinct mode resistance; i.e., coumaplatin but not oxaliplatin induces cell senescence, p53-independent death, immunogenic death T Our findings only provide novel strategy rational design nucleolus-targeted demonstrate accumulating conventional platinum drugs nucleus practical way change its canonical mechanism achieve reduced

Language: Английский

Citations

185
Ribosome Biogenesis: A Central Player in Cancer Metastasis and Therapeutic Resistance DOI Creative Commons
Amr R. Elhamamsy, Brandon J. Metge, Heba Allah Alsheikh

et al.

Cancer Research, Journal Year: 2022, Volume and Issue: 82(13), P. 2344 - 2353

Published: March 18, 2022

Abstract Ribosomes are a complex ensemble of rRNA and ribosomal proteins that function as mRNA translation machines. Ribosome biogenesis is multistep process begins in the nucleolus concludes cytoplasm. The tightly controlled by multiple checkpoint surveillance pathways. Perturbations these checkpoints pathways can lead to hyperactivation ribosome biogenesis. Emerging evidence suggests cancer cells harbor specialized class ribosomes (onco-ribosomes) facilitates oncogenic program, modulates cellular functions, promotes metabolic rewiring. Mutations proteins, processing, assembly factors result ribosomopathies associated with an increased risk developing malignancies. Recent studies have linked mutations aberrant poor prognosis, highlighting ribosome-targeted therapy promising approach for treating patients cancer. Here, we summarize various aspects dysregulation impact resultant onco-ribosomes on malignant tumor behavior, therapeutic resistance, clinical outcome. target, understanding important determinants this will allow improved perhaps selective strategies target biosynthesis.

Language: Английский

Citations

178
Peptide SMIM30 promotes HCC development by inducing SRC/YES1 membrane anchoring and MAPK pathway activation DOI
Yanan Pang, Zhiyong Liu, Huan Han

et al.

Journal of Hepatology, Journal Year: 2020, Volume and Issue: 73(5), P. 1155 - 1169

Published: May 24, 2020

Language: Английский

Citations

176
First-in-Human RNA Polymerase I Transcription Inhibitor CX-5461 in Patients with Advanced Hematologic Cancers: Results of a Phase I Dose-Escalation Study DOI Open Access
Amit Khot, Natalie Brajanovski, Donald P. Cameron

et al.

Cancer Discovery, Journal Year: 2019, Volume and Issue: 9(8), P. 1036 - 1049

Published: May 15, 2019

RNA polymerase I (Pol I) transcription of ribosomal genes (rDNA) is tightly regulated downstream oncogenic pathways, and its dysregulation a common feature in cancer. We evaluated CX-5461, the first-in-class selective rDNA inhibitor, first-in-human, phase dose-escalation study advanced hematologic cancers. Administration CX-5461 intravenously once every 3 weeks to 5 cohorts determined an MTD 170 mg/m2, with predictable pharmacokinetic profile. The dose-limiting toxicity was palmar-plantar erythrodysesthesia; photosensitivity dose-independent adverse event (AE), manageable by preventive measures. induced rapid on-target inhibition transcription, p53 activation detected tumor cells from one patient achieving clinical response. One anaplastic large cell lymphoma attained prolonged partial response patients myeloma diffuse B-cell achieved stable disease as best safe at doses associated benefit dermatologic AEs are manageable. SIGNIFICANCE: inhibitor transcription. This first-in-human establishes feasibility targeting this process, demonstrating single-agent antitumor activity against cancers pharmacokinetics safety profile allowing dosing. Consistent preclinical data, observed TP53 wild-type mutant malignancies.This article highlighted In Issue feature, p. 983.

Language: Английский

Citations

163
IMP dehydrogenase-2 drives aberrant nucleolar activity and promotes tumorigenesis in glioblastoma DOI
Satoshi Kofuji, Akiyoshi Hirayama,

Alexander Otto Eberhardt

et al.

Nature Cell Biology, Journal Year: 2019, Volume and Issue: 21(8), P. 1003 - 1014

Published: Aug. 1, 2019

Language: Английский

Citations

148
Ribosome biogenesis factors—from names to functions DOI Creative Commons
Kerstin Dörner, Chiara Ruggeri, Ivo Zemp

et al.

The EMBO Journal, Journal Year: 2023, Volume and Issue: 42(7)

Published: Feb. 10, 2023

Abstract The assembly of ribosomal subunits is a highly orchestrated process that involves huge cohort accessory factors. Most eukaryotic ribosome biogenesis factors were first identified by genetic screens and proteomic approaches pre‐ribosomal particles in Saccharomyces cerevisiae . Later, research on human synthesis not only demonstrated the requirement for many these conserved evolution, but also revealed involvement additional players, reflecting more complex pathway mammalian cells. Yet, it remained challenge field to assign function reveal their molecular mode action. Over past decade, structural, biochemical, cellular studies have largely filled this gap knowledge led detailed understanding role players during stepwise maturation. Such will be key further understand better treat diseases linked disturbed assembly, including ribosomopathies, as well different types cancer.

Language: Английский

Citations

98
N6-methyladenosine (m6A) in 18S rRNA promotes fatty acid metabolism and oncogenic transformation DOI
Hao Peng, Binbin Chen, Wei Wei

et al.

Nature Metabolism, Journal Year: 2022, Volume and Issue: 4(8), P. 1041 - 1054

Published: Aug. 23, 2022

Language: Английский

Citations

97
Genomic and immune landscape Of metastatic pheochromocytoma and paraganglioma DOI Creative Commons
Bruna Calsina, Elena Piñeiro-Yáñez, Ángel M. Martínez‐Montes

et al.

Nature Communications, Journal Year: 2023, Volume and Issue: 14(1)

Published: Feb. 28, 2023

Abstract The mechanisms triggering metastasis in pheochromocytoma/paraganglioma are unknown, hindering therapeutic options for patients with metastatic tumors (mPPGL). Herein we show by genomic profiling of a large cohort mPPGLs that high mutational load, microsatellite instability and somatic copy-number alteration burden associated ATRX / TERT alterations suitable prognostic markers. Transcriptomic analysis defines the signaling networks involved acquisition competence establishes gene signature related to mPPGLs, highlighting CDK1 as an additional mPPGL marker. Immunogenomics accompanied immunohistochemistry identifies heterogeneous ecosystem at tumor microenvironment level, linked subtype behavior. Specifically, define general immunosuppressive exception being PD-L1 expressing MAML3 -related tumors. Our study reveals canonical markers risk metastasis, suggests usefulness including immune parameters clinical management PPGL prognostication identification who might benefit from immunotherapy.

Language: Английский

Citations

46
High dietary fructose promotes hepatocellular carcinoma progression by enhancing O-GlcNAcylation via microbiota-derived acetate DOI Creative Commons
Peng Zhou,

Wen-yi Chang,

Deao Gong

et al.

Cell Metabolism, Journal Year: 2023, Volume and Issue: 35(11), P. 1961 - 1975.e6

Published: Oct. 4, 2023

Language: Английский

Citations

44
The impact of ribosome biogenesis in cancer: from proliferation to metastasis DOI Creative Commons
Sseu-Pei Hwang, Catherine Denicourt

NAR Cancer, Journal Year: 2024, Volume and Issue: 6(2)

Published: April 8, 2024

Abstract The dysregulation of ribosome biogenesis is a hallmark cancer, facilitating the adaptation to altered translational demands essential for various aspects tumor progression. This review explores intricate interplay between and cancer development, highlighting dynamic regulation orchestrated by key oncogenic signaling pathways. Recent studies reveal multifaceted roles ribosomes, extending beyond protein factories include regulatory functions in mRNA translation. Dysregulated not only hampers precise control global production proliferation but also influences processes such as maintenance stem cell-like properties epithelial-mesenchymal transition, contributing Interference with biogenesis, notably through RNA Pol I inhibition, elicits stress response marked nucleolar integrity loss, subsequent G1-cell cycle arrest or cell death. These findings suggest that cells may rely on heightened transcription, rendering ribosomal synthesis potential therapeutic vulnerability. further targeting vulnerabilities promising strategy disrupt production, presenting opportunities treatment.

Language: Английский

Citations

19