Targeted silencing of SOX2 by an artificial transcription factor showed antitumor effect in lung and esophageal squamous cell carcinoma.

is a transcription factor essential for early mammalian development and for the maintenance of stem cells. Recently, was identified as a lineage specific oncogene, recurrently amplified and activated in lung and esophageal squamous cell carcinoma (SCC). In this study, we have developed a zinc finger-based artificial transcription factor (ATF) to selectively suppress SOX2 expression in cancer cells and termed the system ATF/. We engineered the ATF using six zinc finger arrays designed to target a 19 bp site in the distal promoter and a KOX transcriptional repressor domain. A recombinant adenoviral vector Ad-ATF/ that expresses ATF/ suppressed SOX2 at the mRNA and protein levels in lung and esophageal SCC cells expressing SOX2. In these kinds of cells, Ad-ATF/ decreased cell proliferation and colony formation more effectively than the recombinant adenoviral vector Ad-sh, which expresses short hairpin RNA (sh). Ad-ATF/ induced the cell cycle inhibitor CDKN1A more strongly than Ad-sh. Importantly, the ATF did not suppress the cell viability of normal human cells. Moreover, Ad-ATF/ effectively inhibited tumor growth in a lung SCC xenograft mouse model. These results indicate that ATF/ would lead to the development of an effective molecular-targeted therapy for lung and esophageal SCC.