Fibrillarin-dependent 2′-O-methylation modulates RPS28 ribosome incorporation and oncogenic translation
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.
Authors
- Rebecca Wiberg (ORCID: https://orcid.org/0000-0002-2777-8184)
- Kanchan Kumari (ORCID: https://orcid.org/0000-0001-7546-4174)
- P Groza (ORCID: https://orcid.org/0000-0002-5389-244X)
- Margalida Esteva-Socias (ORCID: https://orcid.org/0000-0002-8047-9298)
- Ana Bosch Campos
- Jonathan D. Gilthorpe (ORCID: https://orcid.org/0000-0002-6884-4774)
- Francesca Tuorto (ORCID: https://orcid.org/0000-0003-1625-1181)
- Pernilla Wikström (ORCID: https://orcid.org/0000-0002-6347-1999)
- Bogdan Pop (ORCID: https://orcid.org/0000-0001-9092-9611)
- Devi Prasad Bhattarai (ORCID: https://orcid.org/0000-0001-9659-4613)
- Virginie Marchand (ORCID: https://orcid.org/0000-0002-8537-1139)
- André Mateus (ORCID: https://orcid.org/0000-0001-6870-0677)
- Katja Petzold (ORCID: https://orcid.org/0000-0001-9470-0347)
- Eliana Destefanis (ORCID: https://orcid.org/0000-0002-3804-6712)
- Johanna Schott (ORCID: https://orcid.org/0000-0002-2684-1305)
- Chloe Williams
- Erik Dassi (ORCID: https://orcid.org/0000-0003-4487-0449)
- Rubin Dasgupta (ORCID: https://orcid.org/0000-0003-4505-7775)
- Yuri Motorin (ORCID: https://orcid.org/0000-0002-8018-334X)
- Francesca Aguiló (ORCID: https://orcid.org/0000-0002-2374-2045)
- Joanna J. Sajkowska
- Carlos Peula
Institutions
- Centre National de la Recherche Scientifique (FR)
- University of Trento (IT)
- Heidelberg University (DE)
- Science for Life Laboratory (SE)
- University Hospital Heidelberg (DE)
- Institute of Oncology Prof. Dr. Ion Chiricuta (RO)
- Skåne University Hospital (SE)
- Ingénierie Moléculaire et Physiopathologie Articulaire (FR)
- University Medical Centre Mannheim (DE)
- Université de Lorraine (FR)
- Umeå University (SE)
Publication Details
- Journal
- Cancer Letters
- Published
- 2025-11-20
- DOI
- https://doi.org/10.1016/j.canlet.2025.218124
- Primary Topic
- RNA modifications and cancer
- Type
- article
- Field-Weighted Citation Impact
- 0.00