SREBP-2-driven transcriptional activation of human SND1 oncogene
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Sandra Armengol1, Enara Arretxe1, Leire Enzunza1, Irati Llorente1, Unai Mendibil1, Hiart Navarro-Imaz1, Begoña Ochoa1, Yolanda Chico1 and María José Martínez1
1Lipids & Liver Research Group, Department of Physiology, Faculty of Medicine and Nursing, University of the Basque Country UPV/EHU, Barrio Sarriena s/n, 48940 Leioa, Vizcaya, Spain
María José Martínez, email: firstname.lastname@example.org
Keywords: SND1; Tudor-SN; gene promoter regulation; SREBP-2; SREBP-1
Received: January 04, 2017 Accepted: September 22, 2017 Published: November 21, 2017
Upregulation of Staphylococcal nuclease and tudor domain containing 1 (SND1) is linked to cancer progression and metastatic spread. Increasing evidence indicates that SND1 plays a role in lipid homeostasis. Recently, it has been shown that SND1-overexpressing hepatocellular carcinoma cells present an increased de novo cholesterol synthesis and cholesteryl ester accumulation. Here we reveal that SND1 oncogene is a novel target for SREBPs. Exposure of HepG2 cells to the cholesterol-lowering drug simvastatin or to a lipoprotein-deficient medium triggers SREBP-2 activation and increases SND1 promoter activity and transcript levels. Similar increases in SND1 promoter activity and mRNA are mimicked by overexpressing nuclear SREBP-2 through expression vector transfection. Conversely, SREBP-2 suppression with specific siRNA or the addition of cholesterol/25-hydroxycholesterol to cell culture medium reduces transcriptional activity of SND1 promoter and SND1 mRNA abundance. Chromatin immunoprecipitation assays and site-directed mutagenesis show that SREBP-2 binds to the SND1 proximal promoter in a region containing one SRE and one E-box motif which are critical for maximal transcriptional activity under basal conditions. SREBP-1, in contrast, binds exclusively to the SRE element. Remarkably, while ectopic expression of SREBP-1c or -1a reduces SND1 promoter activity, knocking-down of SREBP-1 enhances SND1 mRNA and protein levels but failed to affect SND1 promoter activity. These findings reveal that SREBP-2 and SREBP-1 bind to specific sites in SND1 promoter and regulate SND1 transcription in opposite ways; it is induced by SREBP-2 activating conditions and repressed by SREBP-1 overexpression. We anticipate the contribution of a SREBPs/SND1 pathway to lipid metabolism reprogramming of human hepatoma cells.
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