Oklahoma State University, College of Veterinary Medicine, Stillwater, OK, USA, Oklahoma, United States
Abstract: The proto-oncogene c-MYC is a "master regulator" in tumorigenesis, rendering it an attractive therapeutic target, especially in breast cancer. Nevertheless, the intricate network of downstream genes influenced by c-MYC and its absence of identifiable binding pockets present formidable challenges for effective genomic-level deactivation. In this context, elucidating the upstream regulators responsible for c-MYC stabilization and activation has gained paramount importance. We propose a novel strategy of selectively inhibiting deubiquitinases implicated in c-MYC stabilization, given the integral role of the ubiquitin-proteasome system (UPS) in governing c-MYC stability. Our investigations have identified USP10 as a pivotal player in modulating c-MYC stability, particularly within the framework of breast cancer. Our experimental results unequivocally establish that USP10 overexpression leads to c-MYC stabilization, whereas USP10 depletion diminishes c-MYC protein levels. Molecular elucidation of the USP10-c-MYC interaction further refines our understanding of this regulatory mechanism. Crucially, both in vitro and in vivo studies reveal that targeting USP10 significantly impedes the proliferation of breast cancer cells, thereby underscoring its potential as a promising therapeutic target. Our findings shed light on the therapeutic implications of targeting USP10 to regulate c-MYC stability in breast cancer, offering innovative prospects for precision medicine.