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

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

doi:10.18632/oncotarget.21523

Cited by 12 publications

(8 citation statements)

References 47 publications

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“…40 Targeted silencing of SOX2 by an artificial transcription factor shows an anti-tumor effect in ESCC. 41 In the present study, ectopic SOX2 expression promotes migration, invasion, and drug resistance of ESCC cells, while knockdown of SOX2 or WWC1 overexpression diminishes their migration ability and invasive potential.…”

Section: Discussionsupporting

confidence: 50%

SOX2 antagonizes WWC1 to drive YAP1 activation in esophageal squamous cell carcinoma

Chai

Zhao

et al. 2019

Cancer Medicine

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Whether SOX2 and ACTL6A/TP63 interact with the Hippo‐YAP1 pathway in esophageal squamous cell carcinoma (ESCC) remains unclear. Here, we reveal that SOX2, ACTL6A, and TP63 are co‐amplified and upregulated in ESCC samples. Multiple SOX2 binding peaks in the locus of WWC1, a Hippo‐YAP1 regulator, and an inverse correlation between the expression of SOX2 and WWC1 are identified, suggesting direct repression of WWC1 by SOX2. Expression scores of SOX2 are higher in tumors than normal tissues and positively correlated with nuclear YAP1 staining in primary ESCC. Moreover, SOX2 gain‐of‐function significantly promotes nuclear YAP1 expression in ESCC cells while silencing of SOX2 expression inhibits YAP1 activation. SOX2 overexpression leads to a significant enhancement of cell migration and invasion as well as chemoresistance to cisplatin, whereas knockdown of SOX2 or ectopic expression of WWC1 suppresses the SOX2‐induced migration ability and invasive potential. Disruption of this SOX2‐WWC1‐YAP1 axis could be a therapeutic strategy for SOX2‐dependent tumors.

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Section: Discussionsupporting

confidence: 50%

SOX2 antagonizes WWC1 to drive YAP1 activation in esophageal squamous cell carcinoma

Chai

Zhao

et al. 2019

Cancer Medicine

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“…255 Likewise, ATF-based SOX2 inhibition technology also shows impressive effect in growth suppression of SCC in lung and esophageal cancers. 256 However, ZF-ATFs in most cases are delivered by virus, limiting its utility due to poor delivery efficiency and nonspecific nature of viral infections.…”

Section: Sox2-targeting Approachesmentioning

confidence: 99%

Functional characterization of SOX2 as an anticancer target

Zhang

Xiong

Sun

2020

Sig Transduct Target Ther

142

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SOX2 is a well-characterized pluripotent factor that is essential for stem cell self-renewal, reprogramming, and homeostasis. The cellular levels of SOX2 are precisely regulated by a complicated network at the levels of transcription, post-transcription, and posttranslation. In many types of human cancer, SOX2 is dysregulated due to gene amplification and protein overexpression. SOX2 overexpression is associated with poor survival of cancer patients. Mechanistically, SOX2 promotes proliferation, survival, invasion/ metastasis, cancer stemness, and drug resistance. SOX2 is, therefore, an attractive anticancer target. However, little progress has been made in the efforts to discover SOX2 inhibitors, largely due to undruggable nature of SOX2 as a transcription factor. In this review, we first briefly introduced SOX2 as a transcription factor, its domain structure, normal physiological functions, and its involvement in human cancers. We next discussed its role in embryonic development and stem cell-renewal. We then mainly focused on three aspects of SOX2: (a) the regulatory mechanisms of SOX2, including how SOX2 level is regulated, and how SOX2 cross-talks with multiple signaling pathways to control growth and survival; (b) the role of SOX2 in tumorigenesis and drug resistance; and (c) current drug discovery efforts on targeting SOX2, and the future perspectives to discover specific SOX2 inhibitors for effective cancer therapy.

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“…As shown in Figure B, Tandem AZP worked even after incubation at 37 °C for 3 h; otherwise, adding ΦC31 integrase 1.5 and 3 h after the first administration should not have increased only the amount of the target Product (D+A1). In addition, our AZPs and their derivatives have worked at 37 °C in animal cells and bodies as has been demonstrated. ,− …”

Section: Resultsmentioning

confidence: 76%

“…Finally, we must consider the possibility of off-target insertion to nontarget sites by our Tandem AZP. From our previous studies, our AZP derivatives are functional in cells, ,− plants, and animals and specifically bind to their targets. For example, an AZP designed to inhibit the replication of human papillomavirus discriminates between 1 or 2 bp differences in the 19 bp target in animal cells .…”

Section: Discussionmentioning

confidence: 89%

Site-Specific Integration by Recruitment of a Complex of ΦC31 Integrase and Donor DNA to a Target Site by Using a Tandem, Artificial Zinc-Finger Protein

et al. 2018

Self Cite

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To solve the problem of uncontrolled therapeutic gene integration, which is a critical drawback of retroviral vectors for gene therapy, the integration sites of exogenous genes should be precisely controlled not to perturb endogenous gene expression. To accomplish this, we explored the possibility of site-specific integration using two six-finger artificial zinc-finger proteins (AZPs) tandemly conjugated via a flexible peptide linker (designated “Tandem AZP”). A Tandem AZP in which two AZPs recognize specific 19 bp targets in a donor and acceptor DNA was expected to site-specifically recruit the donor DNA to the acceptor DNA. Thereafter, an exogenously added integrase was expected to integrate the donor DNA into a specific site in the acceptor DNA (as it might be in the human genome). We demonstrated in vitro that in the presence of Tandem AZP, ΦC31 integrase selectively integrated a donor plasmid into a target acceptor plasmid not only at 30 °C (the optimum temperature of the integrase) but also at 37 °C (for future application in humans). We expect that with further improvement of our current system, a combination of Tandem AZP with integrase/recombinase will enable site-specific integration in mammalian cells and provide safer gene therapy technology.

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

Cited by 12 publications

References 47 publications

SOX2 antagonizes WWC1 to drive YAP1 activation in esophageal squamous cell carcinoma

SOX2 antagonizes WWC1 to drive YAP1 activation in esophageal squamous cell carcinoma

Functional characterization of SOX2 as an anticancer target

Site-Specific Integration by Recruitment of a Complex of ΦC31 Integrase and Donor DNA to a Target Site by Using a Tandem, Artificial Zinc-Finger Protein

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