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

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. [Display omitted] • Spliceosomal components are translationally regulated during oncogenic stress • MYC promotes SF3A3 translation through an eIF3D-dependent mechanism • SF3A3 selectively regulates MYC-driven splicing and metabolic reprograming • SF3A3 levels impact MYC-induced tumorigenesis and breast cancer plasticity Cieśla et al. uncover a translation-based regulatory layer that steers central spliceosome nodes following oncogenic stress. eIF3D-mediated SF3A3 translation provides an exquisite mechanism to enable cancer-promoting alternative splicing patterns downstream of MYC hyperactivation. This critically rewires cancer cell metabolism and plasticity, highlighting a role for SF3A3 in human breast cancers. [ABSTRACT FROM AUTHOR]