GAB2 Driven Aggressive Phenotype in Oral Cancer: Exploring a Therapeutic Vulnerability Using piRNA and Drug Inhibitor

Abstract

Chemotherapy often induces cellular environment characterized by distinct ncRNA signatures that promote or dodge cytotoxicity. Our study identifies a novel cisplatin-responsive piR-hsa-30937, to inhibit the adaptor protein GAB2 by targeting its 3'UTR, and augments oral cancer cells response to cisplatin. Mechanistically, cisplatin disrupts the OCT1-DNMT1 complex that mediates DNA methylation upstream piR-hsa-30937 genomic locus, to activate piRNA expression. Notably, stable overexpression of GAB2 lacking its 3'UTR effectively rescues the piR-hsa-30937-enhanced cisplatin-induced cytotoxicity to advance a resistant phenotype; for which a drug inhibitor specific to GAB2, was identified. Altogether, our findings reveal a cisplatin-induced disruption of OCT1–DNMT1 repressive complex that regulate piR-hsa-30937 expression to attenuate GAB2-mediated survival signaling in oral cancer1. Importantly, the identification of iodinated-amino acid-derivative as GAB2 inhibitor offers a strategy to overcome GAB2-mediatied aggressiveness and further studies are underway to determine its therapeutic efficacy and synergistic potential with cisplatin to improve treatment outcome in oral cancer.