E3 ligase MAEA-mediated ubiquitination and degradation of PHD3 promotes glioblastoma progression

Abstract

Abstract Glioblastoma (GBM) is the most common malignant glioma with high recurrence rate and a poor prognosis. However, the molecular mechanism of malignant progression of GBM is still unclear. In present study, through proteomic analysis of clinical primary and recurrent glioma samples, we identified that aberrant E3 ligase MAEA expressed in recurrent samples. The results of bioinformatics analysis showed that the high expression of MAEA was related to the recurrence and poor prognosis of glioma and GBM. Functional studies showed that MAEA could promote the proliferation, invasion, stemness and the temozolomide (TMZ) resistance. Mechanistically, the data indicated that MAEA targeted prolyl hydroxylase domain 3 (PHD3) K159 to promote its K48-linked polyubiquitination and degradation, thus enhancing the stability of HIF-1α, thereby promoting the stemness and TMZ resistance of GBM cells through up-regulating CD133. The in vivo experiments further confirmed that knocking down MAEA could inhibit the growth of GBM xenograft tumors. In summary, MAEA enhances the expression of HIF-1α/CD133 through degradation of PHD3 and promotes the malignant progression of GBM.