Targeted silencing of SOX2 by an artificial transcription factor showed antitumor effect in lung and esophageal squamous cell carcinoma
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Etsuko Yokota1, Tomoki Yamatsuji1, Munenori Takaoka1, Minoru Haisa1, Nagio Takigawa2, Noriko Miyake3, Tomoko Ikeda3, Tomoaki Mori4, Serika Ohno4, Takashi Sera4, Takuya Fukazawa1 and Yoshio Naomoto1
1Department of General Surgery, Kawasaki Medical School, Okayama, 700-8505, Japan
2Department of General Internal Medicine 4, Kawasaki Medical School, Okayama, 700-8505, Japan
3General Medical Center Research Unit, Kawasaki Medical School, Okayama, 700-8505, Japan
4Department of Applied Chemistry and Biotechnology, Faculty of Engineering, Okayama University, Okayama, 700-8530, Japan
Takuya Fukazawa, email: [email protected]
Takashi Sera, email: [email protected]
Keywords: artificial transcription factor (ATF), SOX2, squamous cell carcinoma, molecular targeted therapy
Received: July 05, 2017 Accepted: September 20, 2017 Published: October 05, 2017
SOX2 is a transcription factor essential for early mammalian development and for the maintenance of stem cells. Recently, SOX2 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/SOX2. We engineered the ATF using six zinc finger arrays designed to target a 19 bp site in the SOX2 distal promoter and a KOX transcriptional repressor domain. A recombinant adenoviral vector Ad-ATF/SOX2 that expresses ATF/SOX2 suppressed SOX2 at the mRNA and protein levels in lung and esophageal SCC cells expressing SOX2. In these kinds of cells, Ad-ATF/SOX2 decreased cell proliferation and colony formation more effectively than the recombinant adenoviral vector Ad-shSOX2, which expresses SOX2 short hairpin RNA (shSOX2). Ad-ATF/SOX2 induced the cell cycle inhibitor CDKN1A more strongly than Ad-shSOX2. Importantly, the ATF did not suppress the cell viability of normal human cells. Moreover, Ad-ATF/SOX2 effectively inhibited tumor growth in a lung SCC xenograft mouse model. These results indicate that ATF/SOX2 would lead to the development of an effective molecular-targeted therapy for lung and esophageal SCC.
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