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Targeting the CHD3 chromatin remodeler exploits a synthetic lethal vulnerability in dual SMARCA4/SMARCA2-deficient cancers via derepression of PARD3B

ABSTRACT: SWI/SNF-deficient cancers characterized by dual SMARCA4/SMARCA2 loss, including subsets of lung adenocarcinoma and small cell carcinoma of the ovary, hypercalcemic type, represent a major therapeutic challenge. While SMARCA2 paralog-targeting strategies exist for single-subunit loss of SMARCA4, dual SMARCA4/SMARCA2-deficient tumors lack actionable targets. Here, we identify the CHD3/NuRD nucleosome remodeling complex as a critical synthetic lethal vulnerability in these malignancies. Through integrated genomic analyses, we demonstrate that in the absence of SWI/SNF, CHD3 acts as an essential “epigenetic brake” specifically at the enhancer of the cell polarity regulator PARD3B. Loss of CHD3 triggers aberrant chromatin hyper-accessibility and toxic derepression of PARD3B. We further elucidate that PARD3B accumulation is a critical mediator of cell death, which is strongly associated with the attenuation of MYC signaling signatures. This attenuation likely arises from the spatial perturbation of upstream signaling hubs or secondary cellular responses, reducing MYC transcriptional output without degrading the protein itself. Therapeutically, CHD3 depletion led to robust tumor regression in dual SMARCA4/SMARCA2-deficient xenografts, validating the in vivo mechanism of PARD3B upregulation. Collectively, our study defines a novel mode of synthetic lethality driven by “gain-of-toxicity” rather than the loss of survival signals, uncovering a fatal cross-complex dependency. We propose that targeting CHD3 to trigger toxic PARD3B derepression offers a promising therapeutic avenue for treatment-refractory dual SMARCA4/SMARCA2-deficient cancers.

ORGANISM(S): Homo sapiens

PROVIDER: GSE323137 | GEO | 2026/05/21

REPOSITORIES: GEO

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Project description:Epigenetic dysregulation is a major cancer hallmark. Notably, deleterious mutations in genes encoding subunits of SWI/SNF (SWItch Sucrose Non-Fermentable), a major chromatin remodeling complex, occur in approximately 20% of human solid tumors. SWI/SNF mutations have been linked to poor patient outcome and no targeted therapy is currently available to treat patients with SWI/SNF-deficient tumors. SWI/SNF is a modular complex composed of 12-15 subunits encoded by 29 genes, which exist in three forms: canonical BRG1/BRM associated factor (cBAF), polybromo-associated BAF (PBAF) and non-canonical (ncBAF/GBAF), which have variable compositions, targets and effects on chromatin remodeling. Each complex includes core subunits (SMARCC1, SMARCC2, and SMARCD1-3) and one of the two mutually exclusive ATPase subunits (SMARCA2 or SMARCA4). Multiple variant subunits then define each complex’s specificity: ARID1A/B and DPF1-3 for cBAF; ARID2, PBRM1, BRD7 and PHF10 for PBAF; GLTSCR1/1L and BRD9 for ncBAF2. SWI/SNF orchestrates multiple cellular functions, such as transcription regulation, differentiation, proliferation, DNA repair, and immunogenicity. Still, subunit-specific oncogenic mechanisms or targetable dependencies remain poorly understood. To identify intracellular alterations and genetic vulnerabilities induced by SWI/SNF defects at the complex or subunit level, we molecularly and functionally profiled an isogenic panel of HAP1 cell lines knockout (KO) for chromatin remodeling encoding genes, including seven SWI/SNF subunits mutants (SMARCB1-, SMARCA4-, SMARCA2-, ARID1A-, ARID1B-, ARID2- and PBRM1-KO), and six non-SWI/SNF mutants (CREBBP-, BAP1-, EED-, KMT2C-, KMT2D- and SETD2-KO). 70-80% confluent cells were harvested, and total RNA was extracted using Rneasy Mini Kit (Qiagen, 74104) with DNAse treatment, according to the manufacturer’s instructions. Every RNA sample was quantified with a Qubit Fluorometer and evaluated for quality controls using Agilent 2100 Bioanalyzer Instrument (RRID:SCR_018043). After RNA Integrity Number (RIN) quality control, cDNA libraries were generated using the NEBNext Ultra II RNA Library Prep Kit (NEB #E7775) on Bravo Automated Liquid Handling Platform (RRID:SCR_026137). Subsequent indexed RNA sequencing of cDNA libraries with paired-end reads was performed according to the standard Illumina protocol using Illumina NovaSeq 6000 S2 Sequencing System (RRID:SCR_016387), with a target of 100Gb per sample.

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Targeting the CHD3 chromatin remodeler exploits a synthetic lethal vulnerability in dual SMARCA4/SMARCA2-deficient cancers via derepression of PARD3B

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