Abstract
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.
Highlights
Staphylococcal nuclease and tudor domain containing 1 gene (SND1) encodes the conserved multidomain protein SND1, known as TudorSN, TSN or p100 [1,2,3,4]
To determine whether SND1 expression was regulated by sterol regulatory element binding protein (SREBP)-2, human HepG2 cells were cultured under different cellular conditions that modulate SREBP-2 pathway
We confirmed that HepG2 treatment with 10 μM simvastatin or the cell culture in lipoprotein deficient serum (LPDS) medium resulted in the induction of SREBP-2 mRNA and protein expression, concomitant with the increase of transcripts of downstream target genes hydroxymethylglutaryl-coenzyme A reductase (HMGCR) and LDL receptor (LDLR) and unchanged SREBP-1 mRNA content (Figure 1D and 1E)
Summary
Staphylococcal nuclease and tudor domain containing 1 gene (SND1) encodes the conserved multidomain protein SND1, known as TudorSN, TSN or p100 [1,2,3,4]. Emerging findings have demonstrated that SND1 overexpression is linked to progression and malignancy of various types of cancer, such as colon, breast, prostate, lung, glioma, melanoma and liver cancer [17,18,19,20,21,22,23]. These studies documented multiple ways for SND1 to facilitate carcinogenesis. It is in that context where our recent studies in human hepatoma HepG2 cells demonstrated the interaction of nuclear SND1 with the genomic DNA and the recruitment of SND1 to the promoter of a wide number of target genes modulating cell growth, oncogenic transformation, viral infection and metabolic regulation [30]
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