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Mol Cell ; 81(7): 1453-1468.e12, 2021 04 01.
Article in English | MEDLINE | ID: mdl-33662273

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.


Subject(s)
Breast Neoplasms/metabolism , Carcinogenesis/metabolism , Neoplastic Stem Cells/metabolism , Protein Biosynthesis , RNA Splicing Factors/biosynthesis , Spliceosomes/metabolism , Adult , Aged , Aged, 80 and over , Animals , Breast Neoplasms/genetics , Breast Neoplasms/pathology , Carcinogenesis/genetics , Female , Humans , Mice , Mice, Nude , Middle Aged , Proto-Oncogene Proteins c-myc/genetics , Proto-Oncogene Proteins c-myc/metabolism , RNA Splicing Factors/genetics , Spliceosomes/genetics
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