SNPs Give LACTB Oncogene-Like Functions and Prompt Tumor Progression via Dual-Regulating p53

LACTB is identified as a tumor suppressor in several tumors. However, preliminary study reveals that LACTB is overexpressed in osteosarcoma and indicates poor prognosis. Two missense mutations (rs34317102 and rs2729835) exist simultaneously in 92.31% of osteosarcoma patients and cause M5L and R469K double mutations in LACTB, suggesting the biologic function of LACTB protein may be altered in osteosarcoma. Moreover, LACTB^M5L+R469K overexpression can promote malignant progression in different tumors, which suggests that the M5L and R469K mutations confer oncogene-like functions to LACTB. Mechanistically, LACTB^M5L+R469K not only reduces the wild type p53 via enhancing PSMB7 catalytic activity, but also protects p53^R156P protein from lysosomal degradation, which suggesting LACTB^M5L+R469K is a dual-regulator for wt-p53 and mutant p53, and derive oncogene-like functions. More importantly, clavulanate potassium, a bacterial β-lactamase inhibitor, can inhibit osteosarcoma proliferation and sensitize osteosarcoma to cisplatin by binding and blocking LACTB^M5L+R469K. These findings revealed that the M5L and R469K double mutations can diminish the tumor suppressive ability of wild type LACTB and provide oncogene-like functions to LACTB. Inhibiting LACTB^M5L+R469K can suppress the progression of osteosarcoma harbouring wild-type or mutant p53. Clavulanate potassium is a promising drug by targeting LACTB^M5L+R469K-p53 pathway for the treatment of osteosarcoma patients.