Figure 4. A mechanistic model for PTOV1 actions in cancer progression.

PTOV1 can shuttle from the cytoplasm to the nucleus during the progression of the cell cycle. In the cytoplasm, PTOV1 is found at perinuclear and submembranes regions associated to Flotillin-1 and also RACK1 and ribosomes. The latter, likely occur in RNA-protein complexes (RNP) that modulate mRNA translation, including the synthesis of the oncogene c-Jun. In the nucleus, PTOV1 can regulate the expression of a number of genes related to cell proliferation, survival, EMT, and chemoresistance, by direct or indirect (genes shown in parenthesis) association to specific promoters to activate or repress transcription. In turn, c-Jun/AP1 may be directly or indirectly contributing to the action of PTOV1 as a transcription factor. PTOV1 is a repressor for the regulation of HES1, HEY1 and DKK1. These effects result in the negative regulation of Notch signaling in PC and the activation of Wnt/β-catenin signaling in breast cancer. In both tumors, these effects culminate with increased tumor growth, invasion, metastasis, and chemoresistance. PTOV1 as a transcriptional repressor requires the presence of HDACs, suggesting that it is an epigenetic regulator. An additional mechanism for transcriptional repression was suggested for the RAR promoter, where PTOV1 sequesters the activator CBP from MED25, and results in suppression of transcription of RAR targets. The action of PTOV1 of sequestering activators from MED25 might be associated to inhibition of other MED25 targets. The recent identification of the nucleic acid-binding motif (e)AT-hook, at the N-terminal region of PTOV1 gives support to its role in regulation of gene expression by direct DNA or RNA binding.