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The Interaction of SWI/SNF with the Ribosome Regulates Translation and Confers Sensitivity to Translation Pathway Inhibitors in Cancers with Complex Perturbations. | LitMetric

AI Article Synopsis

  • Mutations, deletions, or amplifications of mSWI/SNF subunits are found in over 40% of cancers, making it crucial to understand their roles in normal and cancerous cells for targeted therapy development.
  • The study shows that cancer cells with specific mSWI/SNF mutations are more sensitive to translation pathway inhibitors and have a genetic dependency on translation factors.
  • Additionally, mSWI/SNF subunits are involved in the translation process in the cytoplasm, indicating potential new therapeutic opportunities for treating cancers with altered mSWI/SNF subunits.

Article Abstract

Unlabelled: Subunits from the chromatin remodelers mammalian SWItch/Sucrose Non-Fermentable (mSWI/SNF) are mutated, deleted, or amplified in more than 40% of cancers. Understanding their functions in normal cells and the consequences of cancerous alterations will provide insight into developing new targeted therapies. Here we examined whether mSWI/SNF mutations increase cellular sensitivity to specific drugs. Taking advantage of the DepMap studies, we demonstrate that cancer cells harboring mutations of specific mSWI/SNF subunits exhibit a genetic dependency on translation factors and are sensitive to translation pathway inhibitors. Furthermore, mSWI/SNF subunits were present in the cytoplasm and interacted with the translation initiation machinery, and short-term inhibition and depletion of specific subunits decreased global translation, implicating a direct role for these factors in translation. Depletion of specific mSWI/SNF subunits also increased sensitivity to mTOR-PI3K inhibitors. In patient-derived breast cancer samples, mSWI/SNF subunits expression in both the nucleus and the cytoplasm was substantially altered. In conclusion, an unexpected cytoplasmic role for mSWI/SNF complexes in translation suggests potential new therapeutic opportunities for patients afflicted by cancers demonstrating alterations in their subunits.

Significance: This work establishes direct functions for mSWI/SNF in translation and demonstrates that alterations in mSWI/SNF confer a therapeutic vulnerability to translation pathway inhibitors in cancer cells.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9379364PMC
http://dx.doi.org/10.1158/0008-5472.CAN-21-1360DOI Listing

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