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Fibrillarin-dependent 2′-O-methylation modulates RPS28 ribosome incorporation and oncogenic translation

Groza, Paula ; Kumari, Kanchan ; Esteva-Socias, Margalida ; Schott, Johanna ; Bhattarai, Devi Prasad ; Sajkowska, Joanna J. ; Dasgupta, Rubin ; Peula, Carlos ; Destefanis, Eliana and Williams, Chloe , et al. (2026) In Cancer Letters 639.
Abstract

Fibrillarin (FBL), a core component of the C/D box small nucleolar ribonucleoprotein (snoRNP) complex, catalyzes the 2′-O-methylation (Nm) of the ribose 2′-hydroxyl moiety in ribosomal RNA (rRNA). Distinct Nm patterns contribute to ribosome heterogeneity, which is linked to selective translation of oncogenes. FBL dysregulation generates an aberrant Nm signature in triple-negative breast cancer (TNBC), the most aggressive breast cancer subtype. This study investigated the role of FBL in TNBC via translation-driven mechanisms. Our findings show that FBL knockdown impairs oncogenic traits, triggers metabolic stress, and reduces the translation efficiency of oncogenes, such as metastasis-associated protein 1 ( MTA1 ), interleukin-1... (More)

Fibrillarin (FBL), a core component of the C/D box small nucleolar ribonucleoprotein (snoRNP) complex, catalyzes the 2′-O-methylation (Nm) of the ribose 2′-hydroxyl moiety in ribosomal RNA (rRNA). Distinct Nm patterns contribute to ribosome heterogeneity, which is linked to selective translation of oncogenes. FBL dysregulation generates an aberrant Nm signature in triple-negative breast cancer (TNBC), the most aggressive breast cancer subtype. This study investigated the role of FBL in TNBC via translation-driven mechanisms. Our findings show that FBL knockdown impairs oncogenic traits, triggers metabolic stress, and reduces the translation efficiency of oncogenes, such as metastasis-associated protein 1 ( MTA1 ), interleukin-1 receptor-associated kinase 1 ( IRAK1 ), and thymosin beta 10 ( TMSB10 ). RiboMethSeq confirmed that the rRNA Nm sites exhibited differential sensitivity to FBL depletion. Additionally, FBL knockdown led to alterations in 18S ribosome structure confirmed by SHAPE and specifically reduced RPS28 incorporation into ribosomes. Notably, silencing RPS28 also disrupted both the oncogenic phenotype and downregulated MTA1, IRAK1, and TMSB10 expression. These findings reveal a complex interplay between FBL, rRNA Nm modifications, and RPS28 in shaping oncogenic protein pools and ribosomal composition in TNBC, offering promising insights into therapeutic approaches targeting this aggressive cancer subtype.

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organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
2′-O-methylation, Fibrillarin, IRAK1, MTA1, Ribosome heterogeneity, RPS28, TMSB10, Translation, Triple-negative breast cancer
in
Cancer Letters
volume
639
article number
218124
publisher
Elsevier
external identifiers
  • pmid:41260515
  • scopus:105024875196
ISSN
0304-3835
DOI
10.1016/j.canlet.2025.218124
language
English
LU publication?
yes
additional info
Publisher Copyright: © 2025 The Authors.
id
37c08c1a-5a79-4793-9e70-ecfdcb6340b4
date added to LUP
2026-03-09 12:49:20
date last changed
2026-05-19 00:21:06
@article{37c08c1a-5a79-4793-9e70-ecfdcb6340b4,
  abstract     = {{<p>Fibrillarin (FBL), a core component of the C/D box small nucleolar ribonucleoprotein (snoRNP) complex, catalyzes the 2′-O-methylation (Nm) of the ribose 2′-hydroxyl moiety in ribosomal RNA (rRNA). Distinct Nm patterns contribute to ribosome heterogeneity, which is linked to selective translation of oncogenes. FBL dysregulation generates an aberrant Nm signature in triple-negative breast cancer (TNBC), the most aggressive breast cancer subtype. This study investigated the role of FBL in TNBC via translation-driven mechanisms. Our findings show that FBL knockdown impairs oncogenic traits, triggers metabolic stress, and reduces the translation efficiency of oncogenes, such as metastasis-associated protein 1 ( MTA1 ), interleukin-1 receptor-associated kinase 1 ( IRAK1 ), and thymosin beta 10 ( TMSB10 ). RiboMethSeq confirmed that the rRNA Nm sites exhibited differential sensitivity to FBL depletion. Additionally, FBL knockdown led to alterations in 18S ribosome structure confirmed by SHAPE and specifically reduced RPS28 incorporation into ribosomes. Notably, silencing RPS28 also disrupted both the oncogenic phenotype and downregulated MTA1, IRAK1, and TMSB10 expression. These findings reveal a complex interplay between FBL, rRNA Nm modifications, and RPS28 in shaping oncogenic protein pools and ribosomal composition in TNBC, offering promising insights into therapeutic approaches targeting this aggressive cancer subtype.</p>}},
  author       = {{Groza, Paula and Kumari, Kanchan and Esteva-Socias, Margalida and Schott, Johanna and Bhattarai, Devi Prasad and Sajkowska, Joanna J. and Dasgupta, Rubin and Peula, Carlos and Destefanis, Eliana and Williams, Chloe and Marchand, Virginie and Wikström, Pernilla and Wiberg, Rebecca and Campos, Ana Bosch and Gilthorpe, Jonathan D. and Pop, Bogdan and Mateus, Andre and Motorin, Yuri and Dassi, Erik and Petzold, Katja and Tuorto, Francesca and Aguilo, Francesca}},
  issn         = {{0304-3835}},
  keywords     = {{2′-O-methylation; Fibrillarin; IRAK1; MTA1; Ribosome heterogeneity; RPS28; TMSB10; Translation; Triple-negative breast cancer}},
  language     = {{eng}},
  month        = {{02}},
  publisher    = {{Elsevier}},
  series       = {{Cancer Letters}},
  title        = {{Fibrillarin-dependent 2′-O-methylation modulates RPS28 ribosome incorporation and oncogenic translation}},
  url          = {{http://dx.doi.org/10.1016/j.canlet.2025.218124}},
  doi          = {{10.1016/j.canlet.2025.218124}},
  volume       = {{639}},
  year         = {{2026}},
}