MCCC2 stabilizes LTBP1 via suppressing SMURF1-dependent ubiquitination to drive bone metastasis in prostate cancer.

Prostate cancer (PCa) is one of the most common malignancies in men globally, with bone metastasis being a leading cause of death in advanced disease. Emerging evidence links methylcrotonyl-CoA carboxylase subunit 2 (MCCC2) to the migratory and invasive capacities of PCa cells, but its regulatory mechanisms in bone metastasis and therapeutic potential remain unclear. Here, liquid chromatography-mass spectrometry identified LTBP1 as a direct interacting partner of MCCC2, validated by co-immunoprecipitation and GST pulldown assays. Functional studies demonstrated that MCCC2 promotes PCa cell migration, invasion in vitro, and bone metastasis in vivo. Mechanistically, MCCC2 competitively inhibits SMURF1-mediated ubiquitination and degradation of LTBP1, stabilizing LTBP1 to activate TGF-β signaling. Clinically, high MCCC2 expression correlates with elevated LTBP1 levels, increased bone metastasis incidence, and poor prognosis in PCa patients. These findings reveal that MCCC2 drives PCa bone metastasis via the LTBP1-TGF-β axis, highlighting MCCC2 as a promising therapeutic target for preventing or treating bone metastasis.