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E2F3 upregulation promotes tumor malignancy through the transcriptional activation of HIF-2? in clear cell renal cell carcinoma.

ABSTRACT: The E2F3 transcriptional regulatory pathway plays a major part in multiple-cancer progression, but the specific contributions of this pathway to tumor formation and the progression of clear cell renal cell carcinoma (ccRCC) are not fully understood. Clinically, we demonstrated that E2F3 was overexpressed in advanced tumor features. Moreover, cytoplasmic restoration predicted the poor overall survival of ccRCC patients. As a remarkable oncogene for ccRCC, high HIF-2? levels closely correlated with E2F3 upregulation. We observed in vitro that E2F3 overexpression and knockdown regulated HIF-2? expression. Furthermore, we found that HIF-2? harbored multiple E2F3 binding sites in the promoters. Mechanistically, E2F3 acted to transactivate HIF-2? transcription, which in turn exerted a serial effect on the pivotal epithelial-mesenchymal transition-related genes. The RNA interference-mediated silencing of HIF-2? attenuated E2F3-enhanced cell migration and invasion in vitro and in vivo. Overall, our results identified HIF-2? as a direct target gene for E2F3 upregulation, which was critical for carcinogenesis and progression of ccRCC. Thus, targeting the E2F3-HIF-2? interaction may be a promising approach to ccRCC treatment.

SUBMITTER: Gao Y

PROVIDER: S-EPMC5589559 | biostudies-literature | 2017 Aug

REPOSITORIES: biostudies-literature

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E2F3 upregulation promotes tumor malignancy through the transcriptional activation of HIF-2α in clear cell renal cell carcinoma.

Gao Yu Y Li Hongzhao H Ma Xin X Fan Yang Y Ni Dong D Zhang Yu Y Huang Qingbo Q Liu Kan K Li Xintao X Wang Lei L Yao Yuanxin Y Ai Qing Q Zhang Xu X

Oncotarget 20160713 33

The E2F3 transcriptional regulatory pathway plays a major part in multiple-cancer progression, but the specific contributions of this pathway to tumor formation and the progression of clear cell renal cell carcinoma (ccRCC) are not fully understood. Clinically, we demonstrated that E2F3 was overexpressed in advanced tumor features. Moreover, cytoplasmic restoration predicted the poor overall survival of ccRCC patients. As a remarkable oncogene for ccRCC, high HIF-2α levels closely correlated wit ...[more]

PMID: 28903320

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Project description:BackgroundThe VHL-HIF pathway and lipid droplet accumulation are the main characteristics of clear cell renal cell carcinoma (ccRCC). However, the connection between the two features is largely unknown.MethodsWe used transcriptional sequencing and TCGA database analysis to identify APOL1 as a novel therapeutic target for ccRCC. The oncogenic functions of APOL1 were investigated by cell proliferation, colony formation, migration and invasion assays in ccRCC cells in vitro and xenografts derived from ccRCC cells in vivo. Oil red O staining and quantification were used to detect lipid droplets. Chromatin immunoprecipitation (ChIP) assays and luciferase reporter assays were carried out to identify HIF-2α bound to the promoter of APOL1 and lncRNA LINC02609. RNA-FISH and luciferase reporter assays were performed to determine that LncRNA LINC02609 functions as a competing endogenous RNA to regulate APOL1 expression by sponging miR-149-5p.FindingsRNA-seq data revealed that HIF2α can regulate APOL1 and lncRNA LINC02609 expression. We also found that HIF-2α can bind to the promoter of APOL1 and lncRNA LINC02609 and transcriptionally regulate their expression directly. We further demonstrated that LncRNA LINC02609 functions as a competing endogenous RNA to regulate APOL1 expression by sponging miR-149-5p in ccRCC. Mechanistically, APOL1-dependent lipid storage is required for endoplasmic reticulum (ER) homeostasis and cell viability and metastasis in ccRCC. We also showed that high APOL1 expression correlated with worse clinical outcomes, and knockdown of APOL1 inhibited tumor cell lipid droplet formation, proliferation, metastasis and xenograft tumor formation abilities. Together, our studies identify that HIF2α can regulate the expression of the lipid metabolism related gene APOL1 by direct and indirect means, which are essential for ccRCC tumorigenesis.InterpretationBased on the experimental data, in ccRCC, the HIF-2α/LINC02609/APOL1 axis can regulate the expression of APOL1, thus interfering with lipid storage, promoting endoplasmic reticulum homeostasis and regulating tumor progression in ccRCC. Together, our findings provide potential biomarkers and novel therapeutic targets for future studies in ccRCC.

Dataset Information

E2F3 upregulation promotes tumor malignancy through the transcriptional activation of HIF-2? in clear cell renal cell carcinoma.

Publications

E2F3 upregulation promotes tumor malignancy through the transcriptional activation of HIF-2α in clear cell renal cell carcinoma.

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