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Maria Eugenia Cordero Concha

Biomedical analyst

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

Author

  • Maciej Ciesla
  • Phuong Cao Thi Ngoc
  • Maria Eugenia Cordero Concha
  • Álvaro Sejas Martínez
  • Mikkel Morsing
  • Sowndarya Muthukumar
  • Giulia Beneventi
  • Magdalena Madej
  • Roberto Munita
  • Terese Jönsson
  • Kristina Lövgren
  • Anna Ebbesson
  • Björn Nodin
  • Ingrid Hedenfalk
  • Karin Jirström
  • Johan Vallon-Christersson
  • Gabriella Honeth
  • Johan Staaf
  • Danny Incarnato
  • Kristian Pietras
  • Ana Bosch Campos
  • Cristian Bellodi

Summary, in English

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.

Department/s

  • Division of Molecular Hematology (DMH)
  • StemTherapy: National Initiative on Stem Cells for Regenerative Therapy
  • LUCC: Lund University Cancer Centre
  • EXODIAB: Excellence of Diabetes Research in Sweden
  • Division of Translational Cancer Research

Publishing year

2021-04-01

Language

English

Publication/Series

Molecular Cell

Volume

81

Issue

7

Document type

Journal article

Publisher

Cell Press

Topic

  • Cell and Molecular Biology
  • Biochemistry and Molecular Biology
  • Cancer and Oncology

Keywords

  • DRP1
  • MYC
  • SF3A3
  • alternative splicing
  • cancer plasticity
  • cancer stem cells
  • eIF3D
  • mitochondrial dynamics
  • translation control
  • triple-negative breast cancer

Status

Published

ISBN/ISSN/Other

  • ISSN: 1097-2765