N6-methyladenosine-modified VGLL1 promotes ovarian cancer metastasis through HMGA1/Wnt/β-catenin signaling

Abstract The main causes of death in ovarian cancer (OC) patients are invasive lesion and the spread of metastasis. Determining the biology of cancer metastasis is important to develop novel targeted therapy. The present study aimed to explore the mechanisms that might promote OC metastasis. Here, we identified that VGLL1 expression was remarkably increased in metastatic OC samples. The role of VGLL1 in OC metastasis and tumor growth were examined by cell function assays and mouse models. Mechanistically level, METTL3-mediated N6-methyladenosine (m6A) modification contributed to VGLL1 upregulation in an IGF2BP2 recognition-dependent manner. Furthermore, VGLL1 directly interacts with TEAD4 and co-transcriptionally activates HMGA1. HMGA1 further activates Wnt/β-catenin signaling to enhance OC metastasis by promoting the epithelial-mesenchyme transition traits. Rescue assays indicated that upregulation of HMGA1 was essential for VGLL1-induced metastasis. Additionally, conditional silencing of VGLL1 using a doxycycline-induced knockdown system showed therapeutic potential against metastasis in OC. Importantly, the clinical relevance of IGF2BP2, VGLL1, HMGA1, and β-catenin was conformed in OC tissues. Collectively, these findings showed that m6A-induced VGLL1/ HMGA1/β-catenin axis might play a vital role in OC metastasis and tumor growth. VGLL1 might serve as a prognostic marker and therapeutic target against metastasis of OC.