Profiling of promoter occupancy by the SND1 transcriptional coactivator identifies downstream glycerolipid metabolic genes involved in TNFα response in human hepatoma cells

Abstract

The NF-κB-inducible Staphylococcal nuclease and tudor domain-containing 1 gene (SND1) encodes a coactivator involved in inflammatory responses and tumorigenesis. While SND1 is known to interact with certain transcription factors and activate client gene expression, no comprehensive mapping of SND1 target genes has been reported. Here, we have approached this question by performing ChIP-chip assays on human hepatoma HepG2 cells and analyzing SND1 binding modulation by proinflammatory TNFα. We show that SND1 binds 645 gene promoters in control cells and 281 additional genes in TNFα-treated cells. Transcription factor binding site analysis of bound probes identified motifs for established partners and for novel transcription factors including HSF, ATF, STAT3, MEIS1/AHOXA9, E2F and p300/CREB. Major target genes were involved in gene expression and RNA metabolism regulation, as well as development and cellular metabolism. We confirmed SND1 binding to 21 previously unrecognized genes, including a set of glycerolipid genes. Knocking-down experiments revealed that SND1 deficiency compromises the glycerolipid gene reprogramming and lipid phenotypic responses to TNFα. Overall, our findings uncover an unexpected large set of potential SND1 target genes and partners and reveal SND1 to be a determinant downstream effector of TNFα that contributes to support glycerophospholipid homeostasis in human hepatocellular carcinoma during inflammation.

SND1 acts upstream of SLUG to regulate the epithelial–mesenchymal transition (EMT) in SKOV3 cells

“…In support of our data, Arretxe et al (25) showed that SND1 was potentially able to recognize the promoter region of SLUG through ChIP-on-chip assays. In our previous study, we likewise found that SLUG is a target promoter of SND1 by ChIP-guided ligation and selection assay (17).…”

Oncogenic Role of SND1 in Development and Progression of Hepatocellular Carcinoma

“…However, pdTp treatment also resulted in a decrease in total p65 level indicating that SND1 regulates not only NF-κB activation but also p65 expression. Inflammatory cytokines induce SND1 expression and SND1 promoter contains consensus NF-κB binding sites (38,39). Thus chronic inflammation preceding HCC might result in induction of SND1 which facilitates expansion of TICs and further aggravates inflammation thereby establishing a scenario for the development of HCC.…”

The multifaceted oncogene SND1 in cancer: focus on hepatocellular carcinoma

“…Rapid synthesis of lipids is required for generation of biological membranes and facilitating cancer cell proliferation. SND1 induction with TNFα and subsequent profiling of SND1 promoter activity revealed that SND1 regulates a group of glycerolipid metabolic genes including CHPT1, LPGAT1, PTDSS1 and LPIN1 that are involved in biosynthesis of phophatidylcholine, phosphatidylglycerol, phosphatidylserine and triacylglycerol respectively [58] . SND1 interacts with and inhibits monoglycerolipid lipase (MGLL) [41] , a tumor suppressor that converts monoglycerolipids to glycerols and free fatty acids.…”