Abstract
Quaking (QKI) is an alternative splicing factor that can regulate circRNA formation in the progression of epithelial-mesenchymal transition, but the mechanism remains unclear. High expression of QKI is correlated with short survival time, metastasis, and high clinical stage and pathology grade in hepatocellular carcinoma (HCC). Here we report that transcription of the QKI gene was activated by the Yin-Yang 1 (YY1)/p65/p300 complex, in which YY1 bound to the super-enhancer and promoter of QKI, p65 combined with the promoter, and p300 served as a mediator to maintain the stability of the complex. This YY1/p65/p300 complex increased QKI expression to promote the malignancy of HCC as well as an increased circRNA formation in vitro and in vivo. Hyperoside is one of several plant-derived flavonol glycoside compounds. Through virtual screening and antitumor activity analysis, we found that hyperoside inhibited QKI expression by targeting the YY1/p65/p300 complex. Overall, our study suggests that the regulatory mechanism of QKI depends on the YY1/p65/p300 complex and that it may serve as a potential target for treatment of HCC. SIGNIFICANCE: These findings identify the YY1/p65/p300 complex as a regulator of QKI expression, identifying several potential therapeutic targets for the treatment of HCC.
Highlights
Hepatocellular carcinoma (HCC) is one of the most prevalent and malignant tumors with a high mortality rate worldwide [1, 2]
Our study suggests that the regulatory mechanism of QKI depends on the Yin-Yang 1 (YY1)/p65/p300 complex and that it may serve as a potential target for treatment of HCC
YY1 complex plays a key role in QKI expression in HCC cells PLC-PRF-5 cells were subjected to Chromatin immunoprecipitation (ChIP) analysis to explore the transcriptional regulation of YY1
Summary
Hepatocellular carcinoma (HCC) is one of the most prevalent and malignant tumors with a high mortality rate worldwide [1, 2]. Metastasis is the most important cause of mortality in HCC [3, 4]. Epithelial–mesenchymal transition (EMT) plays a critical role in tumor progression [5, 6], and its pathologic activation during tumor development can lead to the metastasis of primary tumors [3, 7, 8]. CircRNAs are purposefully synthesized and implicated in specific biological roles in EMT. Quaking (QKI) is a distinct functional protein that mediate alternative splicing, which belongs to the STAR family of the. Note: Supplementary data for this article are available at Cancer Research Online (http://cancerres.aacrjournals.org/).
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