RPPH1 drives ovarian cancer cells proliferation via CDK9-c-Myc axis

Abstract

Dysregulation of the proto-oncogene c-Myc is a critical driver of ovarian cancer progression, yet the mechanisms governing its expression remain incompletely characterized. A systematic bioinformatic analysis was used to screen long non-coding RNA involved in the regulation of c-Myc transcriptional activity in ovarian cancer without MYC amplification. The functions of RPPH1 were investigated using loss-of-function and gain-of-function strategies in vitro and in vivo. The therapeutic potential of targeting this axis was evaluated using the CDK9 inhibitor Atuveciclib, alone and in combined with cisplatin, in ovarian cancer xenograft models. RPPH1 expression correlated with c-Myc activity was upregulated in ovarian cancer. High RPPH1 levels predicted worse prognosis. Mechanistically, RPPH1 directly bound CDK9, enhancing its stability and promoting phosphorylation of c-Myc at Ser62. This modification prolongs c-Myc’s half-life and amplifies its transcriptional activity. Atuveciclib abrogated RPPH1-driven c-Myc stabilization and activity, while combination therapy with cisplatin synergistically suppressed RPPH1-high tumour growth in xenograft models. We delineate a non-canonical RPPH1-CDK9-c-Myc axis governing oncoprotein stabilization in ovarian cancer, providing mechanistic insights into lncRNA-mediated post-translational regulation. CDK9 represents a therapeutic target for c-Myc-driven tumours, particularly RPPH1-overexpressing, cisplatin-resistant cases without MYC amplification. The combination of cisplatin and CDK9 inhibitor offers a promising translational strategy.