PI3K/AKT MEDIATED PHOSPHORYLATION OF USF-1 ENHANCES ITS TRANSCRIPTIONAL ACTIVATION OF WBP2 ONCOGENE IN BREAST CANCER CELLS

Abstract

WBP2 plays a vital role in breast tumorigenesis. It positively regulates ER, Hippo and Wnt pathways, which subsequently enhance the transcription of downstream target genes contributing to cancer. WBP2 overexpression was found to promote cell proliferation, migration, invasion and anchorage-independent growth. Understanding the regulation of the expression and activity of WBP2 oncoprotein has implication in cancer therapy. We have reported its regulation at the post-translational and post-transcriptional level. However, its regulation at the transcriptional level is unknown. In this study, the minimal promoter region of WBP2 and the regulatory motif that is critical for its transcription were identified. USF-1 was discovered to be a key transcription factor for WBP2. USF-1 is overexpressed in majority of the breast cancer cell lines and tissues tested and has profound effects on cancer cell proliferation. USF-1 mediated transcription of WBP2 was demonstrated to be inducible by insulin, which led to AKT-mediated phosphorylation of USF-1 that modulated its ability to bind to the WBP2 promoter and activate its transcription. This study sheds new insights into the regulation of the WBP2 oncogene at the transcriptional level by a novel oncogenic transcription factor USF-1. USF-1 is a potential drug target for treatment of WBP2-positive breast cancer.