<< Back to MOTIFvations Blog Home Page

Targeting the CBP/p300: A Novel Therapeutic Approach to SMARCB1-Deficient Tumors?

By Stuart P. Atkinson, Ph.D.

September 9, 2025

Tweet

Do Chromatin Regulators Represent Therapeutic Targets for Certain Tumor Types?

The SWI/SNF chromatin remodeling complex regulates transcription by promoting the opening or closing of the chromatin environment surrounding gene regulatory regions. Mutations in the genes that encode components of the SWI/SNF complex (Mashtalir et al.) occur in ~20% of all cancer patients (Kadoch et al. and Kadoch & Crabtree) and lead to loss-of-function aberrations. More specifically, mutations affecting the gene encoding the SMARCB1 (SWI/SNF Related BAF Chromatin Remodeling Complex Subunit B1) subunit of the SWI/SNF complex prompt the development of rhabdoid tumors and epithelioid sarcomas (Chun et al. and Versteege et al.). While Tazemetostat has been approved for the treatment of SMARCB1-deficient epithelioid sarcoma patients, this EZH2 (histone methyltransferase component of the Polycomb Repressive Complex 2) inhibitor suffers from limited clinical efficacy (Gounder et al.). Can we identify additional chromatin regulators that may represent alternative therapeutic targets for SMARCB1-deficient tumors?

Researchers led by Hideaki Ogiwara (National Cancer Center Research Institute, Tokyo) sought to identify synthetic lethal targets in SMARCB1-deficient cancers using a dual small interfering (si)RNA screening method based on the concept of “simultaneous inhibition of a paralog pair.” Similar functional partners often cause synthetic lethality (Sasaki & Ogiwara); therefore, the authors sought to identify such factors involved in chromatin regulation. Encouragingly, their recent Nature Communications article now highlights the simultaneous inhibition of CBP (CREB-binding protein; CREBBP)/p300 (E1A-binding protein p300; EP300) as a promising therapeutic approach in SMARCB1-deficient tumors (Sasaki et al.).

 Back to Table of Contents

Identifying CBP/p300 as Potential Therapeutic Targets in SMARCB1-Deficient Tumors

The paralog pair of CBP and p300 acts redundantly to acetylate the histone H3 lysine 27 (H3K27) residue and promotes transcription by increasing chromatin accessibility at and recruiting transcriptional regulators to gene regulatory regions (Tie et al., Jin et al., and Rasool et al.). The bromodomain (BRD) of CBP/p300 supports binding to chromatin via acetylated histones while the histone acetyltransferase domain catalyzes the addition of acetyl moieties to H3K27; as such, inhibitors that target the BRD (CCS1477) and HAT (A-485) domains selectively and simultaneously inhibit CBP/p300 function (Lasko et al. and Welti et al.)

The authors first performed a screen to identify paralog pairs of chromatin regulators as a synthetic lethal target for SMARCB1-deficient tumor cells. Their siRNA screen identified CREBBP/EP300, KDM3A/KDM3B, KMT2C/KMT2D, BRPF1/BRPF3, KDM6A/KDM6B, and PRDM8/PRDM13 as previously unidentified paralog pair candidates that display synthetic lethality in SMARCB1-deficient tumor cells. Further analyses revealed that siRNAs targeting CREBBP/EP300 had little impact on SMARCB1-proficient tumor cells but induced synthetic lethality in SMARCB1-deficient tumor cells. Meanwhile, the treatment of cell lines and tumor xenografts derived from SMARCB1-deficient but not SMARCB1-proficient cells with dual CBP/p300 inhibitors suppressed tumor growth. For these reasons, the study focused on the paralog pair of CBP/p300 as a promising synthetic lethal target pair in SMARCB1-deficient tumor cells.

The authors hypothesized that SMARCB1 and CBP/p300 may act cooperatively or competitively to regulate the expression of genes that determine synthetic lethality induced by simultaneous inhibition of CBP/p300 in SMARCB1-deficient cells. Investigating this hypothesis via RNA-sequencing aimed to identify i) genes upregulated in SMARCB1-deficient cells but not in SMARCB1-proficient cells and ii) genes downregulated in SMARCB1-deficient cells treated with a CBP/p300 inhibitor but not in SMARCB1-proficient cells treated with a CBP/p300 inhibitor. This approach identified the KREMEN2 (Kringle-containing transmembrane protein 2) gene – which encodes a single-pass transmembrane protein that plays dual roles (Wnt/β-catenin and apoptosis pathway suppression; Mao et al. and Sumia et al.) – as a candidate gene that determines synthetic lethality.

Further epigenetic analyses employed in the study included CUT&RUN (Cleavage Under Targets and. Release Using Nuclease) and ChIP (Chromatin immunoprecipitation)-sequencing; these approaches revealed that SMARCB1-containing SWI/SNF complexes localized with the repressive H3K27me3 histone modification and the associated methyltransferase EZH2 at the KREMEN2 gene promoter in wild-type cells, resulting in transcriptional downregulation. However, the loss of SMARCB1 expression led to the localization of the permissive H3K27ac histone modification and the recruitment of CBP/p300 to the KREMEN2 locus, resulting in the upregulation of KREMEN2 transcription. KREMEN2 then cooperates with the SMARCA1 chromatin remodeling complex to regulate gene expression; however, the simultaneous inhibition of CBP/p300 prompts KREMEN2 transcriptional downregulation via the suppression of H3K27ac and the reduced recruitment of RNA polymerase II and transcription factors BRD4 and CTCF to the gene promoter and enhancer regions. This mechanism induces apoptosis due to the increased monomerization of KREMEN1, resulting from a failure to interact with KREMEN2 (due to reduced KREMEN2 gene expression), which normally suppresses anti-apoptotic signaling pathways (Sumia et al.). Considering the internalization of membrane proteins by KREMEN1, monomerized KREMEN1 may interact with PI3K (phosphatidylinositol 3-kinase), and then suppress pro-oncogenic PI3K-AKT (protein kinase B) signaling via the internalization of PI3K or PDK1 (phosphoinositide-dependent kinase 1).

Finally, the authors noted that CBP/p300 inhibitors had little effect on the proliferation of normal cells or the body weight of wild-type mice; however, concerns remain regarding side effects due to the genome-wide effects of CBP/p300 inhibitors on the expression of genes other than KREMEN2. Therefore, the authors suggest that KREMEN2 may represent a promising target whose inhibition may induce fewer side effects compared to CBP/p300 inhibition.

 Back to Table of Contents

Active Motif: Aiding Your Epigenetic Studies!

Overall, this exciting epigenetic study – aided by the application of proteinase and phosphatase inhibitor cocktails, recombinant CBP, and ChIP-seq analysis by Active Motif – has helped to identify treatment with CBP/p300 dual inhibitors as a promising therapeutic strategy for SMARCB1-deficient tumor treatment. As such, Active Motif is here to help you determine whether targeting histone acetyltransferases can help to combat certain types of cancer!

 Back to Table of Contents

About the author

Stuart P. Atkinson, Ph.D.

Stuart was born and grew up in the idyllic town of Lanark (Scotland). He later studied biochemistry at the University of Strathclyde in Glasgow (Scotland) before gaining his Ph.D. in medical oncology; his thesis described the epigenetic regulation of the telomerase gene promoters in cancer cells. Following Post-doctoral stays in Newcastle (England) and Valencia (Spain) where his varied research aims included the exploration of epigenetics in embryonic and induced pluripotent stem cells, Stuart moved into project management and scientific writing/editing where his current interests include polymer chemistry, cancer research, regenerative medicine, and epigenetics. While not glued to his laptop, Stuart enjoys exploring the Spanish mountains and coastlines (and everywhere in between) and the food and drink that it provides!

Contact Stuart on X with any questions

Related Articles

<< Back to MOTIFvations Blog Home Page