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

Abstract

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.

Differential Contributions of mSWI/SNF Chromatin Remodeler Sub-Families to Myoblast Differentiation

“…We speculate that the effects of Brd9 KD on myoblast differentiation are due to dysregulation of ribosomal biogenesis and rRNA processing, as seven of the top ten GO terms identified from the pool of genes upregulated in Brd9 KD cells related to rRNA, ribosomes, and translation. mSWI/SNF proteins recently have been linked to altered translational efficiency in cancer cells via direct mechanisms and via inhibition of mSWI/SNF protein function by chemical inhibitors [65,66]; it is possible that altering the gene expression and the processing of ribosome components also promotes altered translational efficiency.…”

Integrated multiomic profiling reveals SWI/SNF subunit-specific pathway alterations and targetable vulnerabilities

“…If most SWI/SNF functions have traditionally been linked to transcription regulation, recent reports [31][32][33][34] and our RIME results suggested that SWI/SNF defects might also alter RNA splicing or translation. We therefore hypothesized that some SWI/SNF-dependent signaling effects might occur uniquely at the protein level and investigated the effects of SWI/SNF subunit defects at both the transcriptome and proteome levels.…”

“…Loss of ARID2 also led to decreased interactions of SMARCC2 with a subset of proteins involved in RNA metabolism or splicing (e.g. DDX24, log2FC = -2.06; SF3B1, log2FC = -3.08; p-adj < 0.05), or translation (e.g., RRP1B, log2FC = -4.51; NOP56, log2FC = -3.61; MYBBP1A, log2FC = -2.26; all p-adj < 0.001), reminiscent of the recently described role of SWI/SNF in alternative splicing in mammals 31,32 , endoplasmic reticulum homeostasis in yeast 33 , and dependency of SWI/SNF-altered cells on translation factors 34 .…”

Epigenetic modulators provide a path to understanding disease and therapeutic opportunity

“…Cytoplasmic examples have been noted for SMARCA4 in corticotroph adenomas ( Animireddy et al 2021 ) and for ARID1B in pancreatic cancer ( Bilodeau et al 2006 ). Recent work has shown that mSWI/SNF subunits are detectible in the cytoplasm and associate with the ribosomal machinery ( Ulicna et al 2022 ). SMARCA4 and PBAF subunits were also found to influence translation through their association with the translational machinery.…”

“…SMARCA4 and PBAF subunits were also found to influence translation through their association with the translational machinery. The cytoplasmic SMARCA4 subunit in particular was shown to correlate with disease progression in primary tumors compared with local recurrences and metastatic breast cancer ( Ulicna et al 2022 ). Together, these results suggest new potential therapeutic targeting for the mSWI/SNF subunits identified in the cytoplasm ( Fig.…”