Epigenetic regulation of the deubiquitinase USP1: a possible mechanism underlying the development of platinum-resistance in ovarian cancer

Platinum (Pt)-based chemotherapy is the gold standard treatment for Epithelial Ovarian Cancer (EOC) and exhibits significant efficacy in the initial stages of therapy. However, the resistance to Pt-based regimens commonly arises for EOC patients, often associated with a poor prognosis and limited therapeutic intervention options. Therefore, addressing the mechanisms that regulate Pt-resistance is still a critical unmet need in EOC management. In this context, we have generated and characterized different Pt-resistant cellular models that shared common features, such as cross-resistance against other chemotherapeutic treatments and ability to form, both in 2D and 3D, colonies and ovary spheres resistant to Pt- treatment which may contribute to their enhanced potential for dissemination and increased aggressiveness. These Pt-Res models are important and useful cellular tools for several ongoing projects since they are currently used in our laboratory to identify new players in Pt-resistance and possible alternative target therapies. We are specifically focused on epigenetic modifications that very recently have been identified as key players in both oncogenesis and chemoresistance with increasing interest toward targeting the Bromodomain and extraterminal domain (BET) protein family. One of the most studied BET proteins is BRD4 which is known to modulate transcriptional activity and it has been implicated in the mechanism of resistance in a wide range of cancers. The present study explores the interplay between BRD4 and USP1, a deubiquitinase that mediates OC resistance to Pt by promoting tumor invasion and epithelial-mesenchymal transition (EMT) features. The transcriptional regulation of USP1 has not been extensively studied, and exploring its epigenetic regulation may offer a promising therapeutic approach. Interestingly, we demonstrated that Pt-sensitive cells displayed a higher transcriptional activation of USP1 in particular under cisplatin (CDDP or Pt) treatment. By means of a panel of BET inhibitors, in particular those targeting BRD4, we showed that Pt-sensitive significantly reverted the transcription of USP1. Moreover, we observed that the combined treatment of BET inhibitors and CDDP reverted USP1 transcriptional induction caused by CDDP alone. Finally, BRD4 was found to directly bind USP1 promoter especially following CDDP treatment, therefore enhancing USP1 transcription. In conclusion, we demonstrated a novel transcriptional regulation of USP1 through BET inhibitors, specifically targeting BRD4, which represents a valuable strategy not only to downmodulate oncogene transcription, but also to potentially control chemoresistance recurrence.