YTHDF1/RNF7/p27 axis promotes prostate cancer progression

Abstract

Abstract Prostate cancer (PCa) is a prevalent malignant tumor of the urinary system and remains the most common cancer among males. In this study, we showed that YTHDF1, one of the reader proteins involved in the N6-methyladenosine (m6A) modification signaling pathway, is highly expressed in PCa cancerous tissues and cells, which correlates with poor clinical outcomes. Our study revealed that YTHDF1 knockdown inhibits tumor cell proliferation, migration, and xenograft tumor formation by decreasing p27 protein stability through proteasome degradation signaling. Consistently, YTHDF1 depletion markedly reduced the clonogenic growth of Pten or/and TP53-deficient organoids. Candidate p27-targeting E3 ubiquitin ligases screening identified RNF7 as the direct downstream target for YTHDF1 in an m6A-dependent manner. The subsequent high translation of RNF7 results in the efficient degradation of the cell cycle inhibitor p27 and malignant tumor cell growth. In addition, we provided evidence showing that YTHDF1 or RNF7 depletion sensitizes tumor cells to chemotherapy drug cisplatin by increasing cellular apoptosis. Our findings revealed that the neddylation inhibitor MLN4924 effectively inhibited prostate cancer progression in vitro and in vivo. Our study highlights the YTHDF1/RNF7/p27 axis as a crucial component in PCa, suggesting its potential as a novel therapeutic target.