IKBKE promotes the ZEB2-mediated EMT process by phosphorylating HMGA1a in glioblastoma

IKBKE (Inhibitor of Nuclear Factor Kappa-B Kinase Subunit Epsilon) is an important oncogenic protein in a variety of tumors, which can promote tumor growth, proliferation, invasion, and drug resistance, and plays a critical regulatory role in the occurrence and progression of malignant tumors. HMGA1a (High Mobility Group A1a) functions as a cofactor for proper transcriptional regulation and is highly expressed in multiple types of tumor cells. ZEB2 (Zinc finger E-box Binding homeobox 2) exerts an active function in epithelial mesenchymal transformation (EMT). In our current study, we confirmed that IKBKE can increase the proliferation, invasion and migration of glioblastoma cells. We then found that IKBKE can phosphorylate HMGA1a at Ser 36 and/or Ser 44, inhibit HMGA1a degradation and induce HMGA1a translocation from the cytoplasm to the nucleus. Crucially, we observed that HMGA1a can regulate ZEB2 gene expression by interacting with ZEB2 promoter regions. Hence, HMGA1a affects ZEB2 expression and promotes ZEB2-related metastasis process. Consequently, IKBKE exerts oncogenic functions via the IKBKE/HMGA1a/ZEB2 axis, and IKBKE may be a prominent biomarker for the treatment of glioblastoma in the future.