Absence of SMARCB1 in rhabdoid tumor cells increases sensitivity to translation inhibition and alters translation efficiency of specific mRNAsn (Ribo-Seq)

Rhabdoid tumors, characterized and driven by the loss of the mSWI/SNF (mammalian SWItch/Sucrose Non-Fermentable) subunit SMARCB1, are very aggressive childhood cancers that can arise in the brain, the kidney, or soft tissues. Cell lines derived from these tumors are specifically sensitivity to the translation inhibitor homoharringtonin (HHT). Having recently demonstrated mSWI/SNF roles in translation, we assessed SMARCB1 potential roles in translation in rhabdoid tumor cells. We first revealed by cell viability assays that rhabdoid tumor cells’ sensitivity to HHT were dependent on the absence of SMARCB1. Polysome profiling and immunoprecipitation experiments demonstrated the interaction of SMARCB1 with the translation machinery. Global translation assays and ribosome profiling experiments further revealed that SMARCB1 re-expression increased global translation and altered translation efficiency of specific mRNAs. Most regulated mRNAs presented an increased translation efficiency and were involved in differentiation. In comparison with the entire transcriptome, these mRNAs presented a longer coding sequence and were enriched in GC. Finally, we demonstrated that SMARCB1 re-expression increased cytoplasmic localization of these mRNAs and that gene encoding these transcripts were bound by SMARCA4 and SMARCC1. In conclusion, this study reveals that the loss of SMARCB1 in rhabdoid tumors has specific consequences on mRNAs translation with potential to unveil new dependencies.