Oncotarget

Research Papers:

NFATc3 plays an oncogenic role in oral/oropharyngeal squamous cell carcinomas by promoting cancer stemness via expression of OCT4

Sung Hee Lee, Calvin Kieu, Charlotte Ellen Martin, Jiho Han, Wei Chen, Jin Seok Kim, Mo K. Kang, Reuben H. Kim, No-Hee Park, Yong Kim and Ki-Hyuk Shin _

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Oncotarget. 2019; 10:2306-2319. https://doi.org/10.18632/oncotarget.26774

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Abstract

Sung Hee Lee1, Calvin Kieu1, Charlotte Ellen Martin1, Jiho Han1, Wei Chen1, Jin Seok Kim2, Mo K. Kang1,3, Reuben H. Kim1,3, No-Hee Park1,3,4, Yong Kim2,3,5 and Ki-Hyuk Shin1,3

1The Shapiro Family Laboratory of Viral Oncology and Aging Research, UCLA School of Dentistry, Los Angeles 90095, CA, USA

2Laboratory of Stem Cell and Cancer Epigenetics, UCLA School of Dentistry, Los Angeles 90095, CA, USA

3UCLA Jonsson Comprehensive Cancer Center, Los Angeles 90095, CA, USA

4Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles 90095, CA, USA

5UCLA Broad Stem Cell Research Center, Box 957357, Los Angeles 90095, CA, USA

Correspondence to:

Ki-Hyuk Shin, email: kshin@dentistry.ucla.edu

Keywords: NFATc3; OSCC; cancer stem cells; OCT4

Received: September 07, 2018     Accepted: February 22, 2019     Published: March 19, 2019

ABSTRACT

Nuclear factor of activated T cells (NFATc1-c4), a family of transcription factors, is involved in many biological processes by regulating various downstream target genes. However, their role in cancer progression remains controversial. We here report that NFATc3 is the dominant isoform of NFAT in human oral epithelial cells, and its expression was increased in a stepwise manner during the progression of oral/oropharyngeal squamous cell carcinoma (OSCC). More importantly, NFATc3 was highly enriched in self-renewing cancer stem-like cells (CSCs) of OSCC. Increased expression of NFATc3 was required for the maintenance of CSC self-renewal, as NFATc3 inhibition suppressed tumor sphere formation in OSCC cells. Conversely, ectopic NFATc3 expression in non-tumorigenic immortalized oral epithelial cells resulted in the acquisition of self-renewal and increase in CSC phenotype, such as enhanced ALDH1HIGH cell population, mobility and drug resistance, indicating the functional role of NFATc3 in the maintenance of CSC phenotype. NFATc3 expression also converted the non-tumorigenic oral epithelial cells to malignant phenotypes. Mechanistic investigations further reveal that NFATc3 binds to the promoter of OCT4, a stemness transcription factor, for its activation, thereby promoting CSC phenotype. Moreover, suppression of OCT4 abrogated CSC phenotype in the cell with ectopic NFATc3 overexpression and OSCC, and ectopic OCT4 expression sufficiently induced CSC phenotype. Our study indicates that NFATc3 plays an important role in the maintenance of cancer stemness and OSCC progression via novel NFATc3-OCT4 axis, suggesting that this axis may be a potential therapeutic target for OSCC CSCs.


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