Pseudogene regulation of connexin 43 loss in cancer: A novel therapeutic target

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Gap junction intercellular communication (GJIC) has a broad physiological function including regulation of cell growth, cell differentiation, and the maintenance of tissue homeostasis. We and others previously found loss of Connexin43 (Cx43) expression in human breast tumor compared to adjacent normal tissue. We also demonstrated that Cxs are important in modulating chemosensitivity of established tumors. Therefore, restoration of Cx43 in cancer cells, which can inhibit cell proliferation and induce cell differentiation, is a promising therapeutic approach. Increasing data suggest that the loss of Cx43 expression in breast cancer may involve many levels, including post-transcriptional gene regulation processes. We analyzed the 3’Untranslated Region (3’UTR)- and 5’Untranslated Region (5’UTR)-mediated regulation of Cx43 mRNA in normal versus breast cancer cell lines and localized sequences that showed differential regulatory features, and we found that a strong positive regulatory element in the Cx43 3’UTR region in non-transformed cells is silent in transformed cells. We recently showed that the Cx43 pseudogene is transcribed preferentially in cancer cells (Oncogene 23(27):4763-70, 2004). We show that the Cx43 pseudogene transcript is associated with polyribosomes, and our data suggest that it is involved in the loss of Cx43 expression in cancer, consistent an emerging paradigm that pseudogenes have regulatory roles. We will formally prove its regulation of Cx43, and we are designing methods to selectively target the pseudogene as an approach to increasing the normal gene, including building the first 3-D molecular model of Cx43 and of the pseudogene, siRNA and mimic peptides, all to take advantage of subtle but definite differences between the normal and pseudogene Cx43. Pseudogene targeting represents an entirely novel anti-cancer therapeutic approach.