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

Etsuko Yokota, Tomoki Yamatsuji, Munenori Takaoka, Minoru Haisa, Nagio Takigawa, Noriko Miyake, Tomoko Ikeda, Tomoaki Mori, Serika Ohno, Takashi Sera, Takuya Fukazawa, Yoshio Naomoto

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6 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)103063-103076
Number of pages14
JournalOncotarget
Volume8
Issue number61
DOIs
Publication statusPublished - Jan 1 2017

Keywords

  • Artificial transcription factor (ATF)
  • Molecular targeted therapy
  • SOX2
  • Squamous cell carcinoma

ASJC Scopus subject areas

  • Oncology

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  • Cite this

    Yokota, E., Yamatsuji, T., Takaoka, M., Haisa, M., Takigawa, N., Miyake, N., Ikeda, T., Mori, T., Ohno, S., Sera, T., Fukazawa, T., & Naomoto, Y. (2017). Targeted silencing of SOX2 by an artificial transcription factor showed antitumor effect in lung and esophageal squamous cell carcinoma. Oncotarget, 8(61), 103063-103076. https://doi.org/10.18632/oncotarget.21523