Absence of SMARCB1 in rhabdoid tumor cells increases sensitivity to translation inhibition and alters translation efficiency of specific mRNAsn
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE268318 | GEO | 2024/10/31
REPOSITORIES: GEO
Similar Datasets
Project description: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.
2024-10-31 | GSE268317 | GEO
Project description: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.
2024-10-31 | GSE268315 | GEO
Project description:Absence of SMARCB1 in rhabdoid tumor cells increases sensitivity to translation inhibition and alters translation efficiency of specific mRNAsn
| PRJNA1116205 | ENA
Project description:Absence of SMARCB1 in rhabdoid tumor cells increases sensitivity to translation inhibition and alters translation efficiency of specific mRNAsn (Ribo-Seq)
| PRJNA1116206 | ENA
Project description:Absence of SMARCB1 in rhabdoid tumor cells increases sensitivity to translation inhibition and alters translation efficiency of specific mRNAs (RNA-Seq)
| PRJNA1116207 | ENA
Project description:SMARCB1 (INI1/SNF5/BAF47), a core subunit of the SWI/SNF (BAF) chromatin-remodeling complex, is inactivated in the large majority of rhabdoid tumors, and germline heterozygous SMARCB1 mutations form the basis for rhabdoid predisposition syndrome. Mouse models validated Smarcb1 as a bona fide tumor suppressor, as Smarcb1 inactivation in mice results in 100% of the animals rapidly developing cancer. SMARCB1 was the first subunit of the SWI/SNF complex found mutated in cancer. More recently, at least seven other genes encoding SWI/SNF subunits have been identified as recurrently mutated in cancer. Collectively, 20% of all human cancers contain a SWI/SNF mutation. Consequently, investigation of the mechanisms by which SMARCB1 mutation causes cancer has relevance not only for rhabdoid tumors, but also potentially for the wide variety of SWI/SNF mutant cancers. Here we discuss normal functions of SMARCB1 and the SWI/SNF complex as well as mechanistic and potentially therapeutic insights that have emerged.
| S-EPMC4195815 | biostudies-literature
Project description:Germline mutations of the SMARCB1 gene predispose to two distinct tumor syndromes: rhabdoid tumor predisposition syndrome, with malignant pediatric tumors mostly developing in brain and kidney, and familial schwannomatosis, with adulthood benign tumors involving cranial and peripheral nerves. The mechanisms by which SMARCB1 germline mutations predispose to rhabdoid tumors versus schwannomas are still unknown. Here, to understand the origin of these two types of SMARCB1-associated tumors, we generated different tissue- and developmental stage-specific conditional knockout mice carrying Smarcb1 and/or Nf2 deletion. Smarcb1 loss in early neural crest was necessary to initiate tumorigenesis in the cranial nerves and meninges with typical histological features and molecular profiles of human rhabdoid tumors. By inducing Smarcb1 loss at later developmental stage in the Schwann cell lineage, in addition to biallelic Nf2 gene inactivation, we generated the first mouse model developing schwannomas with the same underlying gene mutations found in schwannomatosis patients. SMARCB1 mutations predispose to rhabdoid tumors and schwannomas but the mechanisms underlying the tumor type specificity are unknown. Here the authors present new mouse models and show that early Smarcb1 loss causes rhabdoid tumors whereas loss at later stages combined with Nf2 gene inactivation causes shwannomas.
| S-EPMC5563506 | biostudies-literature
Project description:Atypical teratoid rhabdoid tumor (ATRT) is an aggressive and malignant pediatric brain tumor. Polo-like kinase 1 (PLK1) is highly expressed in many cancers and essential for mitosis. Overexpression of PLK1 promotes chromosome instability and aneuploidy by overriding the G2-M DNA damage and spindle checkpoints. Recent studies suggest that targeting PLK1 by small molecule inhibitors is a promising approach to tumor therapy. We investigated the effect of PLK1 inhibition in ATRT. Gene expression analysis showed that PLK1 was overexpressed in ATRT patient samples and tumor cell lines. Genetic inhibition of PLK1 with shRNA potently suppressed ATRT cell growth in vitro. Treatment with the PLK1 inhibitor BI 6727 (Volasertib) significantly decreased cell growth, inhibited clonogenic potential, and induced apoptosis. BI6727 treatment led to G2-M phase arrest, consistent with PLK1's role as a critical regulator of mitosis. Moreover, inhibition of PLK1 by BI6727 suppressed the tumor-sphere formation of ATRT cells. Treatment also significantly decreased levels of the DNA damage proteins Ku80 and RAD51 and increased γ-H2AX expression, indicating that BI 6727 can induce DNA damage. Importantly, BI6727 significantly enhanced radiation sensitivity of ATRT cells. In vivo, BI6727 slowed growth of ATRT tumors and prolonged survival in a xenograft model. PLK1 inhibition is a compelling new therapeutic approach for treating ATRT, and the use of BI6727 should be evaluated in clinical studies.
| S-EPMC5722562 | biostudies-literature
Project description:In this study, DCAF5, a substrate receptor that has been shown to modulate the levels of SWI/SNF subunits, which are components of a chromatin remodeling complex. Here we preformed ubiquitinome proteomics to discover the underlying response of DCAF5 loss on ubiquitylation of SWI/SNF subunits. Furthermore, we determine what sites on SWI/SNF components decrease in ubiquitylation upon DCAF5 loss.
2024-03-25 | PXD046463 | Pride
Project description:Rhabdoid phenotype and loss of SMARCB1 expression in a brain tumor are characteristic features of atypical teratoid/rhabdoid tumors (ATRT). Rare non-rhabdoid brain tumors showing cribriform growth pattern and SMARCB1 loss have been designated cribriform neuroepithelial tumor (CRINET). Small case series suggest that CRINETs may have a relatively favorable prognosis. However, the long-term outcome is unclear and it remains uncertain whether CRINET represents a distinct entity or a variant of ATRT. Therefore, 10 CRINETs were clinically and molecularly characterized and compared with 10 ATRTs of each of three recently described molecular subgroups (i.e. ATRT-TYR, ATRT-SHH and ATRT-MYC) using Illumina Infinium HumanMethylation450 arrays, FISH, MLPA, and sequencing. Furthermore, outcome was compared to a larger cohort of 27 children with ATRT-TYR. Median age of the 6 boys and 4 girls harboring a CRINET was 20 months. On histopathological examination, all CRINETs demonstrated a cribriform growth pattern and distinct tyrosinase staining. On unsupervised cluster analysis of methylation data, all CRINETs examined exclusively clustered within the ATRT-TYR molecular subgroup. As ATRT-TYR, CRINETs mainly showed large heterozygous 22q deletions (9/10) and SMARCB1 mutations of the other allele. In two patients, SMARCB1 mutations were also present in the germline. Estimated mean overall survival in patients with CRINETs was 125 months (95% confidence interval 100-151 months) as compared to only 53 (33-74) months in patients with ATRTs of the ATRT-TYR subgroup (Log-Rank P < 0.05). In conclusion, CRINET represents a SMARCB1-deficient non-rhabdoid tumor, which shares molecular similarities with the ATRT-TYR subgroup but has distinct histopathological features and favorable long-term outcome.
| S-EPMC8028967 | biostudies-literature