FBXO32 Targets c-Myc for Proteasomal Degradation and Inhibits c-Myc Activity

Background: FBXO32 is an E3 ubiquitin ligase that plays important roles in tumorigenesis and muscle atrophy. Results: c-Myc was found to be a target of FBXO32 for proteasomal degradation. Conclusion: FBXO32 targets Lys-326 of c-Myc to form polyubiquitin chains, resulting in inhibition of cell proliferation. Significance: FBXO32 may mediate c-Myc proteasomal degradation. FBXO32 (MAFbx/Atrogin-1) is an E3 ubiquitin ligase that is markedly up-regulated in muscle atrophy. Although some data indicate that FBXO32 may play an important role in tumorigenesis, the molecular mechanism of FBXO32 in tumorigenesis has been poorly understood. Here, we present evidence that FBXO32 targets the oncogenic protein c-Myc for ubiquitination and degradation through the proteasome pathway. Phosphorylation of c-Myc at Thr-58 and Ser-62 is dispensable for FBXO32 to induce c-Myc degradation. Mutation of the lysine 326 in c-Myc reduces c-Myc ubiquitination and prevents the c-Myc degradation induced by FBXO32. Furthermore, overexpression of FBXO32 suppresses c-Myc activity and inhibits cell growth, but knockdown of FBXO32 enhances c-Myc activity and promotes cell growth. Finally, we show that FBXO32 is a direct downstream target of c-Myc, highlighting a negative feedback regulation loop between c-Myc and FBXO32. Thus, FBXO32 may function by targeting c-Myc. This work explains the function of FBXO32 and highlights its mechanisms in tumorigenesis.