Fig. 9: Schematic representation of the mechanism of sensitization to anticancer drugs by USP1 depletion.

Two signaling pathways are involved in ML323-mediated TRAIL sensitization. (1) ML323 decreases miR-216a-5p expression at the transcription level, stabilizes DR5 mRNA, and increases DR5 expression on cancer cell surface. (2) USP1, highly expressed in renal cancer, interacts with survivin and induces deubiquitination of survivin. When USP1 is inhibited by ML323, survivin is ubiquitinated and degraded. Eventually, sensitivity of TRAIL is increased by upregulation of DR5 and downregulation of survivin in ML323 treatment.