Pharmaco-Epigenomic response of Pimozide is mediated through miR-2909

A recent study delves into intricate relationship between microRNAs (miRNAs), specifically focusing on their role in cancer development. miRNAs are highlighted for their capacity to modify genetic profile and modulate epigenetic architecture, establishing regulatory circuit between epigenetic modulation and miRNAs. Notably, antipsychotic drugs, particularly pimozide, is reported to influence miRNA expression, impacting essential processes in cancer development such as cell proliferation and apoptosis. Anti-cancer properties of pimozide have sparked interest in its potential role in cancer treatment, although precise mechanism of its antitumor function remains elusive. The study focuses on a newly discovered miRNA, miR-2909, encoded by the apoptosis antagonizing transcription factor (AATF) gene, which has been implicated in oncogenesis. This research aims to unravel the interplay between pimozide and miR-2909, investigating their influence on epigenetic modulations and their functional relevance to cellular proliferation and apoptosis in cancer cells. Utilizing bioinformatic tools for structural prediction, pharmacokinetic property assessment, and molecular docking interactions, the study reveals a strong binding affinity between pimozide and miR-2909.Validation through various experimental methods, including qRT-PCR, western blotting, immunofluorescence, transient transfection, CHIP assay, and flow cytometry confirms the interplay between pimozide and miR-2909. The results demonstrate a pivotal role in the regulation of genes responsible for cellular proliferation and apoptosis. Additionally, the study uncovers that pimozide's pharmaco-epigenomic response is mediated through miR-2909, promoting DNA methylation and leading to decreased cellular proliferation, increased apoptosis, ROS generation, and altered cell-cycle dynamics. In conclusion, the findings identify pimozide as a potential chemotherapeutic agent acting through the regulation of the oncomiR-2909. Insight Box This study uncovers a novel pharmaco-epigenomic mechanism by which the antipsychotic drug pimozide exerts anti-cancer effects in breast and lung cancer cells. We demonstrate that pimozide downregulates oncogenic miR-2909, leading to the upregulation of DNMT3B, which mediates epigenetic silencing of key proliferation genes and promotes apoptosis. This integrative approach-combining molecular biology, gene expression profiling, and epigenetic analysis-provides new biological insight into the repurposing of psychiatric drugs for cancer therapy. Our findings highlight the therapeutic potential of targeting microRNA-epigenetic interactions and suggest a broader applicability of integrating pharmacology with systems biology to uncover unconventional roles of known drugs in cancer treatment.