Perinucleolar Compartment (PNC) Prevalence as an Independent Prognostic Factor in Pediatric Ewing Sarcoma: A Multi-Institutional Study

Gonzalez, Elizabeth M.; Ahmed, Atif; McCarthy, Laura C; Chastain, Katherine; Habeebu, Sahibu Sultan M; Zapata‐Tarrés, Marta; Cárdenas-Cardós, Rocío; Velasco-Hidalgo, Liliana; Corcuera-Delgado, Celso Tomás; Rodrı́guez-Jurado, Rodolfo; García-Rodríguez, Lilia; Parrales, Alejandro; Iwakuma, Tomoo; Farooqi, Midhat S.; Lee, Brian; Weir, Scott J.; Flatt, Terrie

doi:10.3390/cancers15082230

Cited by 3 publications

(2 citation statements)

References 30 publications

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“…The original identification of RAVER1 revealed its association and co-localization with PTBPs in perinucleolar compartments ( Supplementary Figure S3A ) ( 17 ). Independent studies suggested elevated frequency of PNCs in progressed, metastatic malignancies ( 22 , 23 ). Accordingly, it was tempting to speculate that RAVER1’s role in tumor cell proliferation is associated with its potentially PTBP-dependent modulation of PNC homeostasis.…”

Section: Resultsmentioning

confidence: 99%

“…In s.c. LUAD (A549) xenograft mouse models, the loss of RAVER1 even reduced tumor growth, indicating that RAVER1 serves a rather pro-oncogenic role in lung and presumably other cancers. PTBPs and RAVER1 associate and co-localize in perinucleolar compartments (PNCs, ( 17 )), which were proposed to be enhanced in progressed malignancies ( 22 , 23 ). Thus, it was tempting to speculate that RAVER1 modulates tumor cell fate in a PNC-dependent manner.…”

Section: Discussionmentioning

confidence: 99%

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RAVER1 hinders lethal EMT and modulates miR/RISC activity by the control of alternative splicing

Wedler,

Bley,

Glaß

et al. 2024

Nucleic Acids Research

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The RAVER1 protein serves as a co-factor in guiding the polypyrimidine tract-binding protein (PTBP)-dependent control of alternative splicing (AS). Whether RAVER1 solely acts in concert with PTBPs and how it affects cancer cell fate remained elusive. Here, we provide the first comprehensive investigation of RAVER1-controlled AS in cancer cell models. This reveals a pro-oncogenic role of RAVER1 in modulating tumor growth and epithelial-mesenchymal-transition (EMT). Splicing analyses and protein-association studies indicate that RAVER1 guides AS in association with other splicing regulators, including PTBPs and SRSFs. In cancer cells, one major function of RAVER1 is the stimulation of proliferation and restriction of apoptosis. This involves the modulation of AS events within the miR/RISC pathway. Disturbance of RAVER1 impairs miR/RISC activity resulting in severely deregulated gene expression, which promotes lethal TGFB-driven EMT. Among others, RAVER1-modulated splicing events affect the insertion of protein interaction modules in factors guiding miR/RISC-dependent gene silencing. Most prominently, in all three human TNRC6 proteins, RAVER1 controls AS of GW-enriched motifs, which are essential for AGO2-binding and the formation of active miR/RISC complexes. We propose, that RAVER1 is a key modulator of AS events in the miR/RISC pathway ensuring proper abundance and composition of miR/RISC effectors. This ensures balanced expression of TGFB signaling effectors and limits TGFB induced lethal EMT.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

RAVER1 hinders lethal EMT and modulates miR/RISC activity by the control of alternative splicing

Wedler,

Bley,

Glaß

et al. 2024

Nucleic Acids Research

View full text Add to dashboard Cite

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RAVER1 interconnects lethal EMT and miR/RISC activity by the control of alternative splicing

Wedler

Bley

Glaß

et al. 2023

Preprint

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The RAVER1 protein was proposed to serve as a co-factor in guiding the PTBP-dependent control of alternative splicing (AS). Whether RAVER1 solely acts in concert with PTBPs and how it affects cancer cell fate remained elusive. Here we provide the first comprehensive investigation of RAVER1-controlled AS in cancer cell models and reveal a pro-oncogenic role of RAVER1 in tumor growth. This unravels that RAVER1 guides AS in synergy with PTBPs but more prominently serves PTBP1-independent roles in splicing. In cancer cells, one major function of RAVER1 is the control of proliferation and apoptosis, which involves the modulation of AS events within the miR/RISC pathway. Associated with this regulatory role, RAVER1 antagonizes lethal, TGFB-driven epithelial-mesenchymal-transition (EMT) by limiting TGFB signaling. RAVER1-modulated splicing events affect the insertion of protein interaction modules in factors guiding miR/RISC-dependent gene silencing. Most prominently, in all three human TNRC6 proteins, RAVER1 controls AS of GW-enriched motifs, which are essential for AGO2-binding. Disturbance of RAVER1-guided AS events in TNRC6 proteins and other facilitators of miR/RISC activity compromise miR/RISC activity which is essential to restrict TGFB signaling and lethal EMT.

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Small Molecule with Big Impact: Metarrestin Targets the Perinucleolar Compartment in Cancer Metastasis

Kashyap,

Sharma,

Pandey

et al. 2024

Cells

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Metarrestin (ML246) is a first-in-class pyrrole–pyrimidine-derived small molecule that selectively targets the perinucleolar compartment (PNC). PNC is a distinct subnuclear structure predominantly found in solid tumor cells. The occurrence of PNC demonstrates a positive correlation with malignancy, serving as an indicator of tumor aggressiveness, progression, and metastasis. Various promising preclinical results have led to the clinical translation of metarrestin into a first-in-human trial. This review aims to summarize (i) the current understanding of the structure and function of PNC and its role in cancer progression and metastasis, (ii) key findings from studies examining the effect of metarrestin on various cancers across the translational spectrum, including in vitro, in vivo, and human clinical trial studies, and (iii) the pharmaceutical relevance of metarrestin as a promising anticancer candidate. Furthermore, our molecular docking and MD simulation studies show that metarrestin binds to eEF1A1 and eEF1A2 with a strong and stable affinity and inhibits eEF1A2 more efficiently compared to eEF1A1. The promising results from preclinical studies suggest that metarrestin has the potential to revolutionize the treatment of cancer, heralding a paradigm shift in its therapeutic management.

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Perinucleolar Compartment (PNC) Prevalence as an Independent Prognostic Factor in Pediatric Ewing Sarcoma: A Multi-Institutional Study

Cited by 3 publications

References 30 publications

RAVER1 hinders lethal EMT and modulates miR/RISC activity by the control of alternative splicing

RAVER1 hinders lethal EMT and modulates miR/RISC activity by the control of alternative splicing

RAVER1 interconnects lethal EMT and miR/RISC activity by the control of alternative splicing

Small Molecule with Big Impact: Metarrestin Targets the Perinucleolar Compartment in Cancer Metastasis

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