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

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 PietrasAna Bosch Campos, Cristian Bellodi

Research output: Contribution to journalArticlepeer-review

10 Citations (SciVal)

Abstract

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.
Original languageEnglish
Number of pages28
JournalMolecular Cell
Volume81
Issue number7
DOIs
Publication statusPublished - 2021 Apr 1

Subject classification (UKÄ)

  • 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

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