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Deacetylation Assays to Unravel the Interplay between Sirtuins SIRT2 and Specific Protein-substrates
Published on: February 27, 2016
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SIRT2 Regulates the SMARCB1 Loss-Driven Differentiation Block in ATRT.
Irina Alimova1,2, Dong Wang1,2, John DeSisto1
1Department of Pediatrics and Section of Pediatric Hematology/Oncology/Bone Marrow Transplant Research Laboratories University of Colorado Denver, Anschutz Medical Campus, Aurora, Colorado.
Molecular Cancer Research : MCR
|February 17, 2025
Summary
Targeting SIRT2 offers a promising therapeutic strategy for atypical teratoid rhabdoid tumors (ATRT). Inhibiting SIRT2 combats aggressive pediatric brain tumors by restoring normal gene expression and reversing differentiation block in SMARCB1-deficient cells.
Area of Science:
- Pediatric oncology
- Epigenetics
- Molecular biology
Background:
- Atypical teratoid rhabdoid tumors (ATRT) are aggressive pediatric brain cancers.
- Tumorigenesis is driven by SMARCB1 loss, causing epigenetic dysregulation.
- SMARCB1 loss impacts cell lineage commitment and differentiation.
Purpose of the Study:
- To identify epigenetic factors cooperating with SMARCB1 loss in ATRT.
- To investigate the role of SIRT2 in ATRT cell self-renewal and differentiation.
- To evaluate SIRT2 inhibition as a therapeutic strategy for ATRT.
Main Methods:
- Unbiased epigenome-targeted screening to identify cooperating genes.
- In vitro pluripotency assays and in vivo single-cell RNA transcriptomics.
- Orthotopic murine models treated with SIRT2 inhibitors.
Main Results:
- SIRT2 was identified as a key regulator cooperating with SMARCB1 loss.
- SIRT2 inhibition decreased ATRT cell self-renewal and induced differentiation.
- SIRT2 inhibition restored lost gene expression and reversed differentiation block in vivo.
- Clinically relevant SIRT2 inhibitors demonstrated in vivo efficacy.
Conclusions:
- SIRT2 is a critical dependency in SMARCB1-deficient ATRT cells.
- SIRT2 controls the pluripotency-differentiation switch in ATRT.
- SIRT2 inhibition is a promising therapeutic strategy for ATRT.
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