Research Article: NF-YA transcriptionally activates the expression of SOX2 in cervical cancer stem cells

Date Published: July 31, 2019

Publisher: Public Library of Science

Author(s): Wen-Ting Yang, Zong-Xia Zhao, Bin Li, Peng-Sheng Zheng, Arun Rishi.


Roles for SOX2 have been extensively studied in several types of cancer, including colorectal cancer, glioblastoma and breast cancer, with particular emphasis placed on the roles of SOX2 in cancer stem cell. Our previous study identified SOX2 as a marker in cervical cancer stem cells driven by a full promoter element of SOX2 EGFP reporter. Here, dual-luciferase reporter and mutagenesis analyses were employed, identifying key cis-elements in the SOX2 promoter, including binding sites for SOX2, OCT4 and NF-YA factors in SOX2 promoter. Mutagenesis analysis provided additional evidence to show that one high affinity-binding domain CCAAT box was precisely recognized and bound by the transcription factor NF-YA. Furthermore, overexpression of NF-YA in primitive cervical cancer cells SiHa and C33A significantly activated the transcription and the protein expression of SOX2. Collectively, our data identified NF-YA box CCAAT as a key cis-element in the SOX2 promoter, suggesting that NF-YA is a potent cellular regulator in the maintenance of SOX2-positive cervical cancer stem cell by specific transcriptional activation of SOX2.

Partial Text

Tumor growth, metastasis and recurrence are driven by a small sub-population of cancer stem cells (CSCs)[1]. Most CSCs assays have thus far depended on a variety of different cell surface markers, including CD133, CD44, CD166, CD24 and so on[2]. However, surface markers can only be used to isolate the most common CSCs and these markers are often unstable in many somatic cancers[3]. Additionally, the results obtained with CSCs isolated using the same surface marker are not consistent among laboratories. Due to the instability and scarcity of surface markers in solid tumors, other methodological strategies have been widely explored to identify and isolate CSCs, including nuclear markers[4], side population phenotype[5], sphere formation, and aldehyde dehydrogenase (ALDH) activity assays[6].

Expression of transcription factor SOX2 is one of the hallmarks of embryonic stem cells, induced pluripotent stem cells and CSCs. The relationship between the expression of SOX2 and CSCs population was identified in breast cancer[13], lung cancer[24–26], ovarian cancer[27, 28], and cervical cancer [29]. In our previous study, SOX2-positive cells isolated from the cervical cancer cell lines SiHa and C33A were found to exhibit self-renewal, differentiation, and tumor initiating properties, which are major characteristics of CSCs[7].




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