Oncogenic translation directs spliceosome dynamics revealing an integral role for SF3A3 in breast cancer.

Autor:	Cieśla M; Division of Molecular Hematology, Department of Laboratory Medicine, Lund Stem Cell Center, Faculty of Medicine, Lund University, 22184 Lund, Sweden., Ngoc PCT; Division of Molecular Hematology, Department of Laboratory Medicine, Lund Stem Cell Center, Faculty of Medicine, Lund University, 22184 Lund, Sweden., Cordero E; Division of Translational Cancer Research, Department of Laboratory Medicine, Faculty of Medicine, Lund University, 22363 Lund, Sweden., Martinez ÁS; Division of Molecular Hematology, Department of Laboratory Medicine, Lund Stem Cell Center, Faculty of Medicine, Lund University, 22184 Lund, Sweden., Morsing M; Division of Translational Cancer Research, Department of Laboratory Medicine, Faculty of Medicine, Lund University, 22363 Lund, Sweden., Muthukumar S; Division of Molecular Hematology, Department of Laboratory Medicine, Lund Stem Cell Center, Faculty of Medicine, Lund University, 22184 Lund, Sweden., Beneventi G; Division of Molecular Hematology, Department of Laboratory Medicine, Lund Stem Cell Center, Faculty of Medicine, Lund University, 22184 Lund, Sweden., Madej M; Division of Molecular Hematology, Department of Laboratory Medicine, Lund Stem Cell Center, Faculty of Medicine, Lund University, 22184 Lund, Sweden., Munita R; Division of Molecular Hematology, Department of Laboratory Medicine, Lund Stem Cell Center, Faculty of Medicine, Lund University, 22184 Lund, Sweden., Jönsson T; Division of Molecular Hematology, Department of Laboratory Medicine, Lund Stem Cell Center, Faculty of Medicine, Lund University, 22184 Lund, Sweden., Lövgren K; Division of Oncology, Department of Clinical Sciences, Lund University, Lund, Sweden., Ebbesson A; Division of Oncology, Department of Clinical Sciences, Lund University, Lund, Sweden., Nodin B; Division of Oncology, Department of Clinical Sciences, Lund University, Lund, Sweden., Hedenfalk I; Division of Oncology, Department of Clinical Sciences, Lund University, Lund, Sweden., Jirström K; Division of Oncology, Department of Clinical Sciences, Lund University, Lund, Sweden., Vallon-Christersson J; Division of Oncology, Department of Clinical Sciences, Lund University, Lund, Sweden., Honeth G; Division of Oncology, Department of Clinical Sciences, Lund University, Lund, Sweden., Staaf J; Division of Oncology, Department of Clinical Sciences, Lund University, Lund, Sweden., Incarnato D; Faculty of Science and Engineering, University of Groningen, Groningen, the Netherlands., Pietras K; Division of Translational Cancer Research, Department of Laboratory Medicine, Faculty of Medicine, Lund University, 22363 Lund, Sweden., Bosch A; Division of Oncology, Department of Clinical Sciences, Lund University, Lund, Sweden; Department of Hematology, Oncology and Radiation Physics, Skåne University Hospital, Lund, Sweden. Electronic address: ana.bosch_campos@med.lu.se., Bellodi C; Division of Molecular Hematology, Department of Laboratory Medicine, Lund Stem Cell Center, Faculty of Medicine, Lund University, 22184 Lund, Sweden. Electronic address: cristian.bellodi@med.lu.se.
Jazyk:	angličtina
Zdroj:	Molecular cell [Mol Cell] 2021 Apr 01; Vol. 81 (7), pp. 1453-1468.e12. Date of Electronic Publication: 2021 Mar 03.
DOI:	10.1016/j.molcel.2021.01.034
Abstrakt:	Splicing is a central RNA-based process commonly altered in human cancers; however, how spliceosomal components are co-opted during tumorigenesis remains poorly defined. Here we unravel the core splice factor SF3A3 at the nexus of a translation-based program that rewires splicing during malignant transformation. Upon MYC hyperactivation, SF3A3 levels are modulated translationally through an RNA stem-loop in an eIF3D-dependent manner. This ensures accurate splicing of mRNAs enriched for mitochondrial regulators. Altered SF3A3 translation leads to metabolic reprogramming and stem-like properties that fuel MYC tumorigenic potential in vivo. Our analysis reveals that SF3A3 protein levels predict molecular and phenotypic features of aggressive human breast cancers. These findings unveil a post-transcriptional interplay between splicing and translation that governs critical facets of MYC-driven oncogenesis. Competing Interests: Declaration of interests A.B. received travel grants from Roche and participated in advisory board meetings for Pfizer and Novartis. All other authors declare no competing interests. (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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