Background HOTAIR, as one of the few well-studied oncogenic lncRNAs, is involved in human tumorigenesis and is dysregulated in most human cancers. The transcription co-activator factor YAP1 is broadly expressed in many tissues, and promotes cancer metastasis and progression. However, the precise biological roles of HOTAIR and YAP1 in cancer cells remain unclear. MethodsThe expression levels of HOTAIR and YAP1 were measured by quantitative PCR (qPCR), immunoblotting. Wound-healing and transwell assays were used to examine the invasive abilities of HeLa cells. Luciferase reporter assays and CHIP were used to determine how YAP1 regulates RPL23. A xenograft mouse mode was used to assess the correlation between HOTAIR and YAP1 in vivo. ResultIn this study, we showed that HOTAIR regulates H3K27 histone modi cation in the promoter of miR-200a to mediate miR-200a expression byrecruiting EZH2. YAP1, as a potential target gene of miR-200a, aggravated the effects of miR-200a on the migration and invasion of HeLa cells. YAP1 activated the transcription of RPL23, which is a novel target of YAP1 transcriptional regulation. Agreement with this, the expression of YAP1 and RPL23 was dramatically decreased after injecting HeLa cells transfected with siHOTAIR in a xenograft mouse model. ConclusionThese elucidates that HOTAIR, as an oncogenic lncRNA, recruits EZH2 to reduce miR-200a-3p expression via H3k27 trimethylation in the miR-200a-3p promoter. As a target gene of miR-200a-3p,YAP1 then promotes the migration and invasion of HeLa cells by mediating the downstream transcription of RPL23 which normally functions as a cancer-promoting factor. Accordingly, we propose a novel model of the molecular mechanism by which HOTAIR promotes the migration and invasion of cancer cells involving the miR-200a-3p/YAP1/RPL23 axis. BackgroundIn recent years, lncRNAs have gained widespread attention as a group of non-coding transcripts of > 200 nucleotides that are involved in a wide range of biological processes(1-8). lncRNAs modulate gene expression at the transcriptional, post-transcriptional, translational, or post-translational levels (9-12). Within the last decade, HOTAIR has emerged as a key regulator of carcinogenesis and metastasis, a crucial oncogenic lncRNA contributing to different processes in several cancers (13-15). Howardet.al. rstuncovered a compelling mechanistic basis for HOTAIR in cancer, showing that it interacts with PRC2 to enhance H3K27 trimethylation, and decreases the expression of a large number of genes( 16). HOTAIR, a negative prognostic factor, has been correlated with cancer cell proliferation, apoptosis, invasion, and metastasis in various cancer cell lines(17-20). Moreover, we showed that it may be involved in a diverse range of biological processes by mediating the expression of proteins, such as MKL1, OGFR,. In our previous work, the well-established oncogene YAP1 was found to be signi cantly decreased after HOTAIR inhibition in HepG2 cells using proteomics technology (23). However, there is no evidence investigati...
Purpose Disulfiram (DSF) has been proven safe and shows the promising antitumor effect in preclinical studies. However, the precise mechanism of DSF on tumor is rarely reported. This study aims to fully understand the mechanism of action of DSF with a systems perspective in anticancer effects. Experimental Design SILAC‐based quantitative proteomics strategy was used to systematically identify differential expression proteins (DEPs) after DSF treatment in HeLa cells. Bioinformatical analysis (PANTHER, DAVID, and STRING) were performed to characterize biological functions of DEPs. Functional studies were performed to explore underlying mechanisms of DSF in cancer cells. Results In total, 201 proteins were dysregulated significantly after DSF exposure. Functional studies of hexokinase 2 (HK2), which catalyzed the first irreversible enzymatic step in glucose metabolism, revealed that various phenotypic effects observed after DSF treatment in cancer cells, at least partly, through the regulation of HK2 expression. Conclusions and Clinical Relevance By correlating the proteomics data with these functional studies, the current results provided novel insights into the mechanism underlying DSF function in cancer cells. Meanwhile, these provided theoretical basis for the new use of old drugs in clinical therapy.
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