ArticleActa neuropathologica2021
Inhibition of nuclear export restores nuclear localization and residual tumor suppressor function of truncated SMARCB1/INI1 protein in a molecular subset of atypical teratoid/rhabdoid tumors.
Article in Acta neuropathologica, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 13 papers.
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Who cites it
13 citing papers in PubMed, 14 citations in OpenAlex.
- Paediatric Therapeutic Development Workshop on rhabdoid tumours.British journal of cancer · 2026Review
- Clinicopathological Characterization of Pediatric Atypical Teratoid/Rhabdoid Tumors and an HE-IHC Dual-Path Deep Learning Model for Auxiliary Diagnosis.Diagnostics (Basel, Switzerland) · 2026Article
- The future of targeted therapies for pediatric central nervous system tumors.Neuro-oncology advances · 2026Review
- Targeting the p53 pathway to treat atypical teratoid rhabdoid tumors.Neuro-oncology pediatrics · 2026Article
- Atypical Teratoid Rhabdoid Tumor: How Tumor Diagnostic Methods in the Laboratory Have Evolved over the Past 40 Years.Cancers · 2025Article
- SWI/SNF complexes govern ontology-specific transcription factor function in MYC-subtype atypical teratoid rhabdoid tumor.Neuro-oncology · 2025Article
- SMARCB1-related schwannomatosis and other SMARCB1-associated phenotypes: clinical spectrum and molecular pathogenesis.Familial cancer · 2025Review
- TAR RNA Mimicry of INI1 and Its Influence on Non-Integration Function of HIV-1 Integrase.Viruses · 2025Review
- Review
- Article
- The efficacy of selinexor (KPT-330), an XPO1 inhibitor, on non-hematologic cancers: a comprehensive review.Journal of cancer research and clinical oncology · 2023Review
- Review
- Molecular targeted therapies for pediatric atypical teratoid/rhabdoid tumors.Pediatric investigation · 2022Review
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Authors and funding
19 authors at 9 institutions in 4 countries.
Funding
Abstract
Loss of nuclear SMARCB1 (INI1/hSNF5/BAF47) protein expression due to biallelic mutations of the SMARCB1 tumor suppressor gene is a hallmark of atypical teratoid/rhabdoid tumors (ATRT), but the presence of cytoplasmic SMARCB1 protein in these tumors has not yet been described. In a series of 102 primary ATRT, distinct cytoplasmic SMARCB1 staining on immunohistochemistry was encountered in 19 cases (19%) and was highly over-represented in cases showing pathogenic sequence variants leading to truncation or mutation of the C-terminal part of SMARCB1 (15/19 vs. 4/83; Chi-square: 56.04, p = 1.0E-10) and, related to this, in tumors of the molecular subgroup ATRT-TYR (16/36 vs. 3/66; Chi-square: 24.47, p = 7.6E-7). Previous reports have indicated that while SMARCB1 lacks a bona fide nuclear localization signal, it harbors a masked nuclear export signal (NES) and that truncation of the C-terminal region results in unmasking of this NES leading to cytoplasmic localization. To determine if cytoplasmic localization found in ATRT is due to unmasking of NES, we generated GFP fusions of one of the SMARCB1 truncating mutations (p.Q318X) found in the tumors along with a p.L266A mutation, which was shown to disrupt the interaction of SMARCB1-NES with exportin-1. We found that while the GFP-SMARCB1(Q318X) mutant localized to the cytoplasm, the double mutant GFP-SMARCB1(Q318X;L266A) localized to the nucleus, confirming NES requirement for cytoplasmic localization. Furthermore, cytoplasmic SMARCB1(Q318X) was unable to cause senescence as determined by morphological observations and by senescence-associated β-galactosidase assay, while nuclear SMARCB1(Q318X;L266A) mutant regained this function. Selinexor, a selective exportin-1 inhibitor, was effective in inhibiting the nuclear export of SMARCB1(Q318X) and caused rapid cell death in rhabdoid tumor cells. In conclusion, inhibition of nuclear export restores nuclear localization and residual tumor suppressor function of truncated SMARCB1. Therapies aimed at preventing nuclear export of mutant SMARCB1 protein may represent a promising targeted therapy in ATRT harboring truncating C-terminal SMARCB1 mutations.
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