Journal Article

Targeting dependency on a paralog pair of CBP/p300 against de-repression of KREMEN2 in SMARCB1-deficient cancers

Ogiwara, Hideaki, Kato, Daiki, Takase, Shohei, Yoshida, Hiroshi, Otsubo, Tsuguteru, Murakami, Karin, Sasaki, Mariko

2024

Overview

SMARCB1, a subunit of the SWI/SNF chromatin remodeling complex, is the causative gene of rhabdoid tumors and epithelioid sarcomas. Here, we identify a paralog pair of CBP and p300 as a synthetic lethal target in SMARCB1-deficient cancers by using a dual siRNA screening method based on the “simultaneous inhibition of a paralog pair” concept. Treatment with CBP/p300 dual inhibitors suppresses growth of cell lines and tumor xenografts derived from SMARCB1-deficient cells but not from SMARCB1-proficient cells. SMARCB1-containing SWI/SNF complexes localize with H3K27me3 and its methyltransferase EZH2 at the promotor region of the KREMEN2 locus, resulting in transcriptional downregulation of KREMEN2 . By contrast, SMARCB1 deficiency leads to localization of H3K27ac, 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. Simultaneous inhibition of CBP/p300 leads to transcriptional downregulation of KREMEN2 , followed by apoptosis induction via monomerization of KREMEN1 due to a failure to interact with KREMEN2, which suppresses anti-apoptotic signaling pathways. Taken together, our findings indicate that simultaneous inhibitors of CBP/p300 could be promising therapeutic agents for SMARCB1-deficient cancers. Loss of SMARCB1 has been identified in a number of cancers. Here, the authors report a paralog pair of CBP and p300 as a synthetic lethal target in SMARCB1-deficient cancers. Simultaneous inhibitors of CBP/p300 could be therapeutic agents for SMARCB1-deficient cancers.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 38/1 / 38/109 / 38/15 / 38/23 / 38/39 / 38/77 / 38/79 / 38/89 / 38/91 / 631/337/176 / 631/67/1059 / 631/67/1059/602 / Animals / Apoptosis / Cancer / Cell Line, Tumor / Cell Proliferation - drug effects / Cell Proliferation - genetics / Chromatin Assembly and Disassembly - genetics / Chromatin remodeling / Down-regulation / E1A-Associated p300 Protein - genetics / E1A-Associated p300 Protein - metabolism / Enhancer of Zeste Homolog 2 Protein - antagonists & inhibitors / Enhancer of Zeste Homolog 2 Protein - genetics / Enhancer of Zeste Homolog 2 Protein - metabolism / Gene Expression Regulation, Neoplastic / Genetic screening / Humanities and Social Sciences / Humans / Inhibitors / Localization / Loci / Methyltransferase / Mice / Mice, Nude / multidisciplinary / p300-CBP Transcription Factors - genetics / p300-CBP Transcription Factors - metabolism / Pharmacology / Promoter Regions, Genetic - genetics / Rhabdoid Tumor - genetics / Rhabdoid Tumor - metabolism / Rhabdoid Tumor - pathology / RNA, Small Interfering - genetics / RNA, Small Interfering - metabolism / Science / Science (multidisciplinary) / siRNA / SMARCB1 Protein - genetics / SMARCB1 Protein - metabolism / Transcription / Tumor cell lines / Tumors / Xenograft Model Antitumor Assays / Xenotransplantation