Abstract PR017: Dissecting the role of CHD1 as a key regulator of pro-metastatic transcriptional reprogramming in BRCA2-mutant prostate cancer

Abstract Prostate cancer (PCa) is the most commonly diagnosed cancer and the second leading cause of cancer-related death in American men. Men with germline BRCA2 mutations are at especially high risk (19%-61% by age 80) of developing PCa. Loss of BRCA2 impairs homologous recombination repair (HRR), resulting in genomic instability and enhanced tumor progression. Our laboratory previously performed a whole-genome CRISPR-Cas9 screen in a BRCA2 mutant cell line under cisplatin induced stress. This screen identified Chromodomain Helicase DNA-binding protein 1 (CHD1) as the top gene whose loss promoted cell survival under DNA damage stress. CHD1 is a chromatin remodeler that is deleted in approximately 15% PCas and is strongly linked to metastatic disease. However, how its loss drives tumor progression, particularly in BRCA2-deficient PCas, remains poorly understood. To address this, we carried out RNA-seq analysis in castration-resistant prostate cancer (CRPC) cell line PC-3 following knockdown of CHD1 and BRCA2, individually and in combination. Notably, depletion of CHD1 in BRCA2-deficient cells resulted in the upregulation of gene signatures associated with hypoxia and epithelial-mesenchymal-transition (EMT). Functional validation using wound healing and migration assays demonstrated that CHD1 loss significantly enhanced the migration ability of PC-3 cells (including BRCA2-deficient) compared to controls. In keeping with increased EMT, we also see high vimentin expression in CHD1-depleted PC3. Furthermore, Causal Inference Enrichment (CIE) analysis of the transcriptomic data pointed to significant activation of transcription factors (TFs) FOSL1 and SOX9 after CHD1 knockdown compared to control cells. To assess clinical relevance, we analyzed RNA-seq data from the Stand Up To Cancer (SU2C) database. This analysis revealed that CHD1-low tumors exhibited upregulation of multiple oncogenic pathways, especially EMT, angiogenesis, apical junction, and IL2-STAT5 signaling, consistent with our in vitro observations. Finally, genetically engineered mouse model (GEMM)-derived prostate organoids from B2PPt (Brca2flox/flox;P53flox/flox;Ptenflox/flox) and B2CPPt (Brca2flox/flox; Chd1flox/flox;P53flox/flox;Ptenflox/flox) mice, after Adeno-Cre infection, revealed higher Fosl1, along with EMT marker vimentin in B2CPPt organoids compared to B2PPt, supporting FOSL1-dependent lineage plasticity and activation of EMT programs upon CHD1 loss in BRCA2-mutant prostate cells. Collectively, these findings indicate that CHD1 loss, either independently or in the context of BRCA2 deficiency, promotes oncogenic phenotypes through activation of FOSL1-dependent lineage plasticity and EMT programs that favor metastasis. Ongoing work dissects how CHD1 loss reshapes chromatin accessibility to reprogram transcriptional networks and drives oncogenic signaling and metastatic pathways in PCa, with particular relevance to BRCA2-deficient PCa. Citation Format: Jingzhu Hao, Shailja Pathania, Miklos Diossy, Kourosh Zarringhalam, Changmeng Cai, Zoltan Szallasi. Dissecting the role of CHD1 as a key regulator of pro-metastatic transcriptional reprogramming in BRCA2-mutant prostate cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Innovations in Prostate Cancer Research and Treatment; 2026 Jan 20-22; Philadelphia PA. Philadelphia (PA): AACR; Cancer Res 2026;86(2_Suppl):Abstract nr PR017.