NONO Is a Negative Regulator of SOX2 Promoter

Abstract

Background/Aim: Sex determining region Y (SRY)box 2 (SOX2) is a transcription factor essential for the maintenance of proliferation and self-renewal of cancer stem cells and is associated with breast cancer initiation. Regulation of cancer stem cell plasticity by SOX2 requires both positive and negative SOX2 transcription factors, but the negative regulator is still largely unknown. Materials and Methods: SOX2 promoter-binding proteins were identified by liquid chromatography-mass spectrometry/mass spectrometry, luciferase assay, and chromatin immunoprecipitation. The effects of one such transcription factor on SOX2 expression was investigated by knockdown and overexpression experiments. Results: Non-POU domain-containing octamerbinding protein (NONO) (also known as 54-kDa nuclear RNA-binding protein, P54NRB) was identified as a SOX2 promoter-binding protein and a negative regulator of SOX2 expression. Its activity was controlled by its coiled-coil domain and the C-terminal domain. Conclusion: These results suggest that NONO acts as a key regulator of SOX2 transcription through the repression of SOX2 promoter activity in breast cancer cells. Sex-determining region Y-box 2 (SOX2) is a transcription factor that is associated with tumor malignancy of glioma cells, ovarian cancer, head and neck cancer, and breast cancer (1). In breast cancer, the expression level of SOX2 is associated with tumor size and the number of metastatic lymph nodes (2). SOX2 overexpression also enhances tumorinitiating activity in breast cancer cell lines (3). These reports suggest that SOX2 is an important factor for maintenance of cancer stem cells (CSCs). Recently, it was pointed out that CSCs have plasticity and may reversibly change their behavior between non-CSCs and CSCs (4). Therefore, if the properties of CSCs are controlled by SOX2, SOX2 expression must not only be induced but also suppressed. In many cancer types, SOX2 mRNA expression is mainly controlled by its promoter (5, 6), and nuclear transcription factor Y subunit alpha, transcription adaptor putative zinc finger, and glioma associated oncogene family zinc finger 1 have been reported as enhancers of the SOX2 promoter (7-9). However, the negative regulators of SOX2 transcriptional are largely unknown in breast cancer. While non-pituitary-specific factor, octamer transcription factor, neural un-coordinated-86 (POU) domain-containing octamer-binding protein (NONO; previously known as 54-kDa nuclear RNA-binding protein/P54NRB) is an RNA splicing factor, it also binds to DNA using a POU-like element and regulates transcription through a coiled-coil domain (10). NONO interacts with SOX9 and induces transcription of collagen, type II, alpha 1 gene, which is a differentiation marker of chondrocytes, by binding to the promoter (11). NONO also induces transcription of sterol regulatory element-binding protein-1a in breast cancer (12). On the other hand, NONO acts as a transcriptional repressor 359 This article is freely accessible online.

Establishment and characterization of a new spontaneously immortalized ER−/PR−/HER2+ human breast cancer cell line, DHSF-BR16

“…These genes possess features that well contribute to the definition of specific characteristics of DHSF-BR16 cells. It has been recently demonstrated that SOX2, a transcription factor essential for the maintenance of proliferation and self-renewal of cancer stem cells, is related to breast cancer initiation 49 . YAP1, the core protein of the Hippo signaling pathway, has been associated with malignancy and immunosuppression.…”