The Related Transcriptional Enhancer Factor-1 Isoform, TEAD4 ₂₁₆, Can Repress Vascular Endothelial Growth Factor Expression in Mammalian Cells

Abstract

Increased cellular production of vascular endothelial growth factor (VEGF) is responsible for the development and progression of multiple cancers and other neovascular conditions, and therapies targeting post-translational VEGF products are used in the treatment of these diseases. Development of methods to control and modify the transcription of the VEGF gene is an alternative approach that may have therapeutic potential. We have previously shown that isoforms of the transcriptional enhancer factor 1-related (TEAD4) protein can enhance the production of VEGF. In this study we describe a new TEAD4 isoform, TEAD4 ₂₁₆, which represses VEGF promoter activity. The TEAD4 ₂₁₆ isoform inhibits human VEGF promoter activity and does not require the presence of the hypoxia responsive element (HRE), which is the sequence critical to hypoxia inducible factor (HIF)-mediated effects. The TEAD4 ₂₁₆ protein is localized to the cytoplasm, whereas the enhancer isoforms are found within the nucleus. The TEAD4 ₂₁₆ isoform can competitively repress the stimulatory activity of the TEAD4 ₄₃₄ and TEAD4 ₁₄₈ enhancers. Synthesis of the native VEGF ₁₆₅ protein and cellular proliferation is suppressed by the TEAD4 ₂₁₆ isoform. Mutational analysis indicates that nuclear or cytoplasmic localization of any isoform determines whether it acts as an enhancer or repressor, respectively. The TEAD4 ₂₁₆ isoform appears to inhibit VEGF production independently of the HRE required activity by HIF, suggesting that this alternatively spliced isoform of TEAD4 may provide a novel approach to treat VEGF-dependent diseases.