Abstract 1701: ABI1 regulates prostate tumor plasticity through chromatin remodeling and transcriptional regulation

Abstract

Abstract Background: Prostate cancer remains a challenging issue affecting men worldwide. In contrast to localized disease, metastatic prostate cancer tumor is incurable. Progression to metastatic disease is characterized by tumor heterogeneity and plasticity regulated by epigenetic changes of tumor cells. While tumor heterogeneity is often associated with gene mutations, tumor plasticity is ascribed to transcriptional regulation and chromatin activity. The latter is modulated by treatment of prostate cancer leading to treatment resistance. Here, we identified a novel mechanism of epigenetic regulation in prostate cancer by an actin regulatory and signaling protein, Abelson Interactor 1 (ABI1). Methods: To demonstrate the ABI1-DNA binding, we employed in vitro binding assays, NMR spectroscopy, and ChIP-seq. from cells expressing alternatively spliced isoforms of ABI1 that contain or lack the DNA binding HHR domain. To determine the ABI1 interactions with several transcriptional factors, we used immunoprecipitation and/or proximity ligation assay (PLA). We used ATAC sequencing to determine the chromatin accessibility in the presence or absence of ABI1 gene. RNA-seq established the activity of transcriptional factors and signaling pathways regulated by ABI1. Results: Using NMR spectroscopy, we established that ABI1 demonstrated DNA binding dependent on the presence of alternatively spliced Exon 4. Exon 4 is located within the homeobox homology region (HHR). The DNA binding activity was confirmed using in vitro binding assays; the assay results confirmed the role of ABI1 HHR. Moreover, cells lacking ABI1 or expressing ABI1 lacking Exon 4 show low accessibility and activity of chromatin. In contrast, cells expressing ABI1 containing Exon 4 show active chromatin. RNA-seq analysis demonstrated that ABI1 regulated transcription in an Exon 4-dependent manner. Conclusions: We uncovered a role of ABI1 in chromatin stability, that is dependent on the presence of the DNA binding region. Notably, ABI1's contribution to transcriptional activity occurs via a transient yet precisely defined interaction between its intrinsically disordered region and DNA. This regulatory control plays a pivotal role in managing tumor plasticity by establishing connections between the actin cytoskeleton, cellular signaling, and transcriptional regulation. Based on these findings, we propose that ABI1 functions as an epigenetic regulator, maintaining transcriptional homeostasis in prostate cancer. Citation Format: Leszek Kotula. ABI1 regulates prostate tumor plasticity through chromatin remodeling and transcriptional regulation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1701.