Oncogenic translation directs spliceosome dynamics revealing an integral role for SF3A3 in breast cancer
Maciej Cieśla, Phuong Cao Thi Ngoc, Eugenia Cordero, 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, Cristian Bellodi
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.