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mSWI/SNF interacts with the ribosome and its inhibition/mutations alter translation and sensitize to mTOR/PI3K inhibitors

Livia Ulicna, Samuel C. Kimmey, Christopher M. Weber, Grace M. Allard, View ORCID ProfileSean C. Bedall, Gerald R. Crabtree, Gregory R. Bean, View ORCID ProfileCapucine Van Rechem
doi: https://doi.org/10.1101/2021.05.10.443459
Livia Ulicna
1Department of Pathology, Stanford University, Stanford, CA 94305, USA
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Samuel C. Kimmey
1Department of Pathology, Stanford University, Stanford, CA 94305, USA
2Department of Developmental Biology, Stanford University, Stanford, CA 94305, USA
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Christopher M. Weber
1Department of Pathology, Stanford University, Stanford, CA 94305, USA
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Grace M. Allard
1Department of Pathology, Stanford University, Stanford, CA 94305, USA
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Sean C. Bedall
1Department of Pathology, Stanford University, Stanford, CA 94305, USA
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  • ORCID record for Sean C. Bedall
Gerald R. Crabtree
1Department of Pathology, Stanford University, Stanford, CA 94305, USA
2Department of Developmental Biology, Stanford University, Stanford, CA 94305, USA
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Gregory R. Bean
1Department of Pathology, Stanford University, Stanford, CA 94305, USA
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Capucine Van Rechem
1Department of Pathology, Stanford University, Stanford, CA 94305, USA
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  • ORCID record for Capucine Van Rechem
  • For correspondence: cvrechem@stanford.edu
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Abstract

The chromatin remodelers mammalian SWItch/Sucrose Non-Fermentable (mSWI/SNF) subunits are mutated, deleted or amplified in more than 40% of cancers. Understanding their functions in normal cells and the consequences of cancer’s alterations will lead to path toward new targeted therapies. Canonically, mSWI/SNF complexes regulate the structure of chromatin, however they likely have additional functions which could be relevant in carcinogenesis. Here, we highlight the substantial alteration of mSWI/SNF subunits expression in both the nucleus and cytoplasm in breast cancer cases. We demonstrate mSWI/SNF cytoplasmic localization and interaction with the translation initiation machinery. Short-term inhibition and depletion of specific subunits alter protein synthesis, implicating a direct role for these factors in translation. Inhibition and depletion of specific subunits increase sensitivity to mTOR-PI3K inhibitors, suggesting a potential therapeutic opportunity for diseases harboring mutations in these complexes. Indeed, SMARCA4 pathogenic mutations decrease protein synthesis. Furthermore, taking advantage of the DepMap studies, we demonstrate cancer cells harboring mutations of specific mSWI/SNF subunits exhibit a genetic dependency on translation factors and are particularly sensitive to translation pathway inhibitors. In conclusion, we report an unexpected cytoplasmic role for mSWI/SNF in protein synthesis, suggesting potential new therapeutic opportunities for patients afflicted by cancers demonstrating alterations in its subunits.

Statement of significance This study establishes direct functions for mSWI/SNF in protein synthesis. mSWI/SNF inhibition, depletion and cancer mutations alter translation and increase sensitivity to translation pathway inhibitors, illustrating the potential for new therapeutic strategies.

Competing Interest Statement

G.R.C. if a founder and stockholder of Foghorn Therapeutics. Other authors declare no potential conflicts of interest.

Footnotes

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  • Conflict of Interest G.R.C. if a founder and stockholder of Foghorn Therapeutics. Other authors declare no potential conflicts of interest.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.
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Posted May 10, 2021.
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mSWI/SNF interacts with the ribosome and its inhibition/mutations alter translation and sensitize to mTOR/PI3K inhibitors
Livia Ulicna, Samuel C. Kimmey, Christopher M. Weber, Grace M. Allard, Sean C. Bedall, Gerald R. Crabtree, Gregory R. Bean, Capucine Van Rechem
bioRxiv 2021.05.10.443459; doi: https://doi.org/10.1101/2021.05.10.443459
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mSWI/SNF interacts with the ribosome and its inhibition/mutations alter translation and sensitize to mTOR/PI3K inhibitors
Livia Ulicna, Samuel C. Kimmey, Christopher M. Weber, Grace M. Allard, Sean C. Bedall, Gerald R. Crabtree, Gregory R. Bean, Capucine Van Rechem
bioRxiv 2021.05.10.443459; doi: https://doi.org/10.1101/2021.05.10.443459

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