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Targeting Dependency on a Paralog Pair of CBP/p300 against De-repression of KREMEN2 in SMARCB1-Deficient Cancers

ABSTRACT: SMARCB1, a subunit of the SWI/SNF chromatin remodeling complex, is the causative gene of pediatric and juvenile cancers such as rhabdoid tumors and epithelioid sarcomas. Here, we used a dual siRNA screening method based on the “simultaneous inhibition of a paralog pair” concept to identify a paralog pair comprising acetyltransferases CBP and p300 as a synthetic lethal target in SMARCB1-deficient cancers. Treatment with CBP/p300 dual inhibitors suppressed growth of cell lines and tumor xenografts derived from SMARCB1-deficient cells but not SMARCB1-proficient cells. SMARCB1-containing SWI/SNF complexes localized with H3K27me3 (a marker of transcriptional repression) and its methyltransferase, EZH2, at the promotor region of the KREMEN2 locus. By contrast, SMARCB1 deficiency led to localization of H3K27ac (a marker of transcriptional promotion) and recruitment of its acetyltransferases CBP and p300 at the KREMEN2 locus, resulting in transcriptional upregulation of KREMEN2, which cooperates with the SMARCA1 chromatin remodeling complex instead of SMARCB1-deficient residual SWI/SNF complexes. Simultaneous inhibition of CBP/p300 led to transcriptional downregulation of KREMEN2 and then induced apoptosis by monomerization of KREMEN1 due to a failure to interact with KREMEN2, which suppressing anti-apoptotic signaling pathways. Taken together, our findings indicate that simultaneous inhibitors of CBP/p300 could be promising therapeutic agents for SMARCB1-deficient cancers.

ORGANISM(S): Homo sapiens

PROVIDER: GSE237043 | GEO | 2024/04/29

REPOSITORIES: GEO

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