METAP2 inhibits K48-linked ubiquitination of YTHDF2 to promote ovarian cancer progression

Abstract

Methionine aminopeptidase 2 (METAP2), one of the two enzymes responsible for removing the N-terminal methionine from nascent proteins, has emerged as a potential drug target for cancer therapy. Yet, its role in ovarian cancer remains largely elusive. Here, we demonstrated that METAP2 is upregulated in ovarian cancer tissues and is associated with poor clinical outcomes. Consistently, METAP2 knockdown significantly suppresses the proliferation and migration of ovarian cancer cells in vivo and in vitro. Mechanistically, co-immunoprecipitation analysis identified YTHDF2 as a key interactor of METAP2. METAP2 interacts with YTHDF2 and attenuates its K48-linked ubiquitination at lysine 245, thereby preventing proteasomal degradation. Importantly, using AlphaFold3 algorithm, we elucidated and then experimentally validated that the Gln342 to Phe361 region of YTHDF2 interacts with the Thr240 to Gly358 region of METAP2. Furthermore, we identified BMF, LXRA, and HIVEP2 as functionally critical downstream targets of the METAP2-YTHDF2 axis, which are essential for ovarian cancer cells proliferation, migration and invasion. Additionally, we validated the therapeutic potential of the METAP2 inhibitor ZGN-1061 in ovarian cancer models. In conclusion, our findings reveal that METAP2 drives ovarian cancer progression by promoting YTHDF2-mediated mRNA decay of BMF/LXRA/HIVEP2, highlighting METAP2 as a potential therapeutic target for ovarian cancer.