SREBP-2-driven transcriptional activation of human SND1 oncogene

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.

Insights Into SND1 Oncogene Promoter Regulation

“…In this regard, our own work revealed that SND1 is a target gene for SREBPs. The activation of SREBP-2 in HepG2 cells cultured in the presence of the cholesterol synthesis inhibitor simvastatin or in a lipoprotein-deficient medium resulted in an increment of SND1 promoter activity and transcript levels (79). ChIP and mutational assays confirmed the functional binding of SREBP-2 to two sites in the proximal promoter sequence containing the SRE −60 and E-box −230 motifs while SREBP-1 binding is restricted to the region with the regulatory element SRE −60 (Figure 3B).…”

The multifaceted oncogene SND1 in cancer: focus on hepatocellular carcinoma

“…NF-κB binding site is located within the proximal 300 bp segment of SND1 promoter and confers TNFα-mediated induction of SND1 [13] [ Figure 1B]. SREBP-2 binds to a proximal promoter region containing a serum response element and an enhancer box motif and induces SND1 expression upon cholesterol depletion [16] . Activated Smad2 and Smad3 bind to SND1 promoter and confer TGFβ-medicated induction of SND1 expression [17] [ Figure 1B].…”

“…Cholesterol is another component of the lipid core in both LDs and lipoproteins, the synthesis of which is regulated by SND1. Under conditions of cholesterol depletion, SREBP2, a regulator of cholesterol uptake and synthesis activates SND1 [16] . Overexpression of SND1 results in increased cholesterogenesis, metabolically coupled to cholesterol esterification, causing an increase in cholesteryl ester levels [57] .…”

The Potential of Isoprenoids in Adjuvant Cancer Therapy to Reduce Adverse Effects of Statins

“…SREBP-2 and HMGCR were overexpressed in cisplatin-resistant A2780 epithelial ovarian cancer cells (Zheng et al, 2018). SREBP-2 promotes the expression of Staphylococcal nuclease and tudor domain containing 1 gene that is associated with the progression and malignancy of colon, breast, prostate, lung, glioma, skin, and liver cancers (Armengol et al, 2017), providing potential new applications for tocotrienols in cisplatin-resistant cancers. Mevalonate rescues the effect of statin, but not that of tocotrienol, on prostate cancer cell viability, consistent with tocotrienol-mediated increase in the degradation of nuclear, mature SREBP-2, which maintains cholesterol homeostasis through transcriptional regulation of enzymes in cholesterol biosynthesis and uptake beyond HMGCR (Krycer et al, 2012).…”