MLF2 stabilized by PIM3 promotes metastasis in osteosarcoma

Osteosarcoma is the most common primary malignant bone cancer. This form of cancer has a high rate of lung metastasis, and it lacks a therapeutic target. Here, by combining an in vivo CRISPR activation screen with the interactome of STUB1, a tumor suppressor of osteosarcoma, we report that MLF2 promotes osteosarcoma metastasis by interfering with the binding between BiP and IRE1a to activate the IRE1a/XBP1-S-MMP9 axis. Moreover, E3 ligase STUB1 can ubiquitinate MLF2 at K119, resulting in the proteasomal degradation of MLF2, and the phosphorylation of MLF2 at Ser65 by PIM3 promotes its stabilizing interaction with USP21. Our findings demonstrate that the PIM3/MLF2 axis plays a key role in osteosarcoma lung metastasis, suggesting that PIM3 inhibitors may be used to treat osteosarcoma patients with high levels of PIM3.