Staphylococcal Nuclease and Tudor Domain Containing 1 (SND1 Protein) Promotes Hepatocarcinogenesis by Inhibiting Monoglyceride Lipase (MGLL)

Abstract

Staphylococcal nuclease and tudor domain containing 1 (SND1) is overexpressed in multiple cancers, including hepatocellular carcinoma (HCC), and functions as an oncogene. This study was carried out to identify novel SND1-interacting proteins to better understand its molecular mechanism of action. SND1-interacting proteins were identified by a modified yeast two-hybrid assay. Protein-protein interaction was confirmed by co-immunoprecipitation analysis. Staphylococcal nuclease and tudor domain containing 1 (SND1) is a multifunctional protein regulating transcription, RNA interference (RNAi) and mRNA splicing, editing, and stability and functions as an oncogene in multiple cancers (1). SND1 overexpression has been observed in cancers of liver, colon, breast, brain, and prostate, and overexpression and knockdown studies have confirmed that SND1 promotes the hallmarks of cancer, such as proliferation, invasion, epithelialmesenchymal transition, angiogenesis, and metastasis (2-8).As a pleiotropic protein, SND1 promotes tumorigenesis in multiple ways. We documented that SND1 promotes RNA-induced silencing complex activity in hepatocellular carcinoma (HCC) 4 cells thus facilitating oncogenic miRNA-mediated degradation of tumor suppressor mRNAs and thereby facilitating hepatocarcinogenesis (2). In HCC cells, SND1 promotes angiogenesis by activating a linear pathway involving NF-B, miRNA-221, angiogenin, and CXCL16, and it promotes epithelial-mesenchymal transition via angiotensin II type 1 receptor (AT1R) and TGF␤ signaling pathway (7,8). Studies in breast cancer cells have identified SND1 as a downstream target of TGF␤ signaling where it promotes metastasis by increasing E3 ubiquitin ligase Smurf1 leading to RhoA ubiquitination and degradation (9). Additionally SND1 is required for expansion and activity of tumor-initiating cells in the breast cancer model (6). In colon cancer cells, SND1 promotes tumorigenesis by activating Wnt/␤-catenin pathway (4). SND1 functions as an anti-apoptotic protein, and cleavage of SND1 by caspases is necessary during drug-induced apoptosis (10). These findings indicate that SND1 promotes tumorigenesis by diverse mechanisms, and more in-depth studies are necessary to better understand the molecular mechanisms by which SND1 exerts its oncogenic function.Triglycerides are broken down into fatty acids and glycerol by sequential action of multiple enzymes (11). Triglyceride lipase breaks down triglyceride into diacylglycerols, which are further broken down to monoacylglycerols by hormone-sensitive lipase. Monoglyceride lipase (MGLL) finally breaks down

The multifaceted oncogene SND1 in cancer: focus on hepatocellular carcinoma

“…Chronic inflammation is a critical event in HCC pathogenesis and induction by inflammatory cytokines might underlie the overexpression of SND1 in human HCC patients. Overexpression and knockdown studies in human HCC cells have demonstrated that SND1 promotes proliferation, migration, invasion and in vivo tumorigenesis [38][39][40][41] . As a component of the RISC in HCC cells, SND1 promotes oncogenic miRNA-mediated degradation of tumor suppressor mRNAs [38] [ Figure 2].…”

“…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. Thus, SND1 causes an increase in glycerolipid levels in cells by causing an increase in their synthesis or preventing their catabolism in hepatocytes [ Figure 3].…”

“…In HCC cells, SND1 activates NF-κB, resulting in induction of miR-221 and angiogenic factors angiogenin and CXCL16 that promote tumor angiogenesis [40] . Monoglyceride lipase (MGLL) inhibits Akt activation and SND1 interacts with and induces degradation of MGLL, resulting in activation of Akt and subsequent augmentation of cell proliferation and cell cycle progression by human HCC cells [41] . SND1 downregulates IGFBP3 expression in human HCC cells that might result in activation of insulin-like growth factor (IGF) signaling, a frequent event in human hepatocarcinogenesis [42] .…”

Transcriptomic reappraisal identifies MGLL overexpression as an unfavorable prognosticator in primary gastrointestinal stromal tumors

“…Nomura et al reported that aggressive cancer lines of various cellular lineages and primary ovarian carcinomas and melanomas may hijack overexpressed MGLL to drive tumorigenesis by remodeling fatty acids to yield a signaling network enriched with pro-oncogenic lipid metabolites such as lipophosphatidic acid and prostaglandins [14]. By contrast, the reduced expression or even absence of MGLL has been reported in various common carcinomas, with MGLL proposed as a potential tumor suppressor [18, 19] because of its growth-suppressive effect on cell colony formation [19]. Notably, contradictory results regarding the oncogenic versus tumor suppressive functions of MGLL have been reported for the same tumor type, such as colorectal cancers [19-21].…”

“…However, the regulation of MGLL expression may operate at multiple levels. For instance, MGLL was reported as a potential tumor suppressor in hepatocellular carcinomas, associated with its loss of protein expression, which was posttranslationally dictated by SND1-promoted ubiquitination for proteasome-mediated proteolysis [18]. As revealed in the datasets of cancer genomic projects [22], MGLL amplification is common in various tumor types such as prostatic carcinomas with neuroendocrine phenotypes [23] and pancreatic ductal adenocarcinomas [24].…”