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Podoplanin is highly expressed in human cancers. However, mechanisms regulating podoplanin expression remain elusive. Here we show that podoplanin promotes tumorigenesis of oral squamous cell carcinoma (OSCC) and precancerous cells both in vitro and in vivo, and the ErbB3-binding protein-1 (Ebp1) can be activated in oral tumorigenesis and can serve as a transcriptional activator to drive podoplanin expression in the malignant progression. Most of the OSCC cell lines have no detectable podoplanin protein in low-density cultures. However, the protein becomes detectable in high-density cultures and is required for in-vivo tumor formation of OSCC and oral premalignancies. In a high-density culture condition, podoplanin expression can be triggered at both mRNA and protein levels. In this condition, we showed that Ebp1 is upregulated, translocated from the cytoplasm to the nucleus and binds to the podoplanin promoter to result in a dramatic increase of podoplanin mRNA and protein. Ebp1 downregulation significantly reduced podoplanin expression levels in OSCC cells with a decreased anchorage-dependent growth, invasion and wound healing. Conversely, Ebp1 overexpression enhanced these malignant features through podoplanin upregulation both in vitro and in vivo. In 81 patients with oral premalignant lesions, we found that Ebp1 expression is strongly related to OSCC development. We conclude that Ebp1 has a key role in the upregulation of podoplanin and may contribute to oral tumorigenesis.