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Loss of HSulf-1: The Missing Link between Autophagy and Lipid Droplets in Ovarian Cancer.

ABSTRACT: Defective autophagy and deranged metabolic pathways are common in cancer; pharmacologic targeting of these two pathways could provide a viable therapeutic option. However, how these pathways are regulated by limited availability of growth factors is still unknown. Our study shows that HSulf-1 (endosulfatase), a known tumor suppressor which attenuates heparin sulfate binding growth factor signaling, also regulates interplay between autophagy and lipogenesis. Silencing of HSulf-1 in OV202 and TOV2223 cells (ovarian cancer cell lines) resulted in increased lipid droplets (LDs), reduced autophagic vacuoles (AVs) and less LC3B puncta. In contrast, HSulf-1 proficient cells exhibit more AVs and reduced LDs. Increased LDs in HSulf-1 depleted cells was associated with increased ERK mediated cPLA2^S505 phosphorylation. Conversely, HSulf-1 expression in SKOV3 cells reduced the number of LDs and increased the number of AVs compared to vector controls. Furthermore, pharmacological (AACOCF3) and ShRNA mediated downregulation of cPLA2 resulted in reduced LDs, and increased autophagy. Finally, in vivo experiment using OV202 Sh1 derived xenograft show that AACOCF3 treatment effectively attenuated tumor growth and LD biogenesis. Collectively, these results show a reciprocal regulation of autophagy and lipid biogenesis by HSulf-1 in ovarian cancer.

SUBMITTER: Roy D

PROVIDER: S-EPMC5294412 | biostudies-literature | 2017 Feb

REPOSITORIES: biostudies-literature

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Loss of HSulf-1: The Missing Link between Autophagy and Lipid Droplets in Ovarian Cancer.

Roy Debarshi D Mondal Susmita S Khurana Ashwani A Jung Deok-Beom DB Hoffmann Robert R He Xiaoping X Kalogera Eleftheria E Dierks Thomas T Hammond Edward E Dredge Keith K Shridhar Viji V

Scientific reports 20170207

Defective autophagy and deranged metabolic pathways are common in cancer; pharmacologic targeting of these two pathways could provide a viable therapeutic option. However, how these pathways are regulated by limited availability of growth factors is still unknown. Our study shows that HSulf-1 (endosulfatase), a known tumor suppressor which attenuates heparin sulfate binding growth factor signaling, also regulates interplay between autophagy and lipogenesis. Silencing of HSulf-1 in OV202 and TOV2 ...[more]

PMID: 28169314

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Project description:BackgroundLoss of the endosulfatase HSulf-1 is common in ovarian cancer, upregulates heparin binding growth factor signaling and potentiates tumorigenesis and angiogenesis. However, metabolic differences between isogenic cells with and without HSulf-1 have not been characterized upon HSulf-1 suppression in vitro. Since growth factor signaling is closely tied to metabolic alterations, we determined the extent to which HSulf-1 loss affects cancer cell metabolism.ResultsIngenuity pathway analysis of gene expression in HSulf-1 shRNA-silenced cells (Sh1 and Sh2 cells) compared to non-targeted control shRNA cells (NTC cells) and subsequent Kyoto Encyclopedia of Genes and Genomics (KEGG) database analysis showed altered metabolic pathways with changes in the lipid metabolism as one of the major pathways altered inSh1 and 2 cells. Untargeted global metabolomic profiling in these isogenic cell lines identified approximately 338 metabolites using GC/MS and LC/MS/MS platforms. Knockdown of HSulf-1 in OV202 cells induced significant changes in 156 metabolites associated with several metabolic pathways including amino acid, lipids, and nucleotides. Loss of HSulf-1 promoted overall fatty acid synthesis leading to enhance the metabolite levels of long chain, branched, and essential fatty acids along with sphingolipids. Furthermore, HSulf-1 loss induced the expression of lipogenic genes including FASN, SREBF1, PPARγ, and PLA2G3 stimulated lipid droplet accumulation. Conversely, re-expression of HSulf-1 in Sh1 cells reduced the lipid droplet formation. Additionally, HSulf-1 also enhanced CPT1A and fatty acid oxidation and augmented the protein expression of key lipolytic enzymes such as MAGL, DAGLA, HSL, and ASCL1. Overall, these findings suggest that loss of HSulf-1 by concomitantly enhancing fatty acid synthesis and oxidation confers a lipogenic phenotype leading to the metabolic alterations associated with the progression of ovarian cancer.ConclusionsTaken together, these findings demonstrate that loss of HSulf-1 potentially contributes to the metabolic alterations associated with the progression of ovarian pathogenesis, specifically impacting the lipogenic phenotype of ovarian cancer cells that can be therapeutically targeted.

Project description:The origin and deep evolution of retroviruses remain largely unclear. It has been proposed that retroviruses might have originated from a Ty3/Gypsy retrotransposon, but all known Ty3/Gypsy retrotransposons are only distantly related to retroviruses. Retroviruses and some plant Athila/Tat elements (within Ty3/Gypsy retrotransposons) independently evolved a dual RNase H domain and an env/env-like gene. Here, we reported the discovery of a novel lineage of retrotransposons, designated Odin retrotransposons, in the genomes of eight sea anemones (order Actinaria) within the Cnidaria phylum. Odin retrotransposons exhibited unique genome features, encoding a dual RNase H domain (like retroviruses) but no env gene (like most Ty3/Gypsy retrotransposons). Phylogenetic analyses based on reverse transcriptase showed that Odin retrotransposons formed a sister group to lokiretroviruses, and lokiretroviruses and Odin retrotransposons together were sister to canonical retroviruses. Moreover, phylogenetic analyses based on RNase H and integrase also supported the hypothesis that Odin retrotransposons were sisters to lokiretroviruses. Lokiretroviruses and canonical retroviruses did not form a monophyletic group, indicating that lokiretroviruses and canonical retroviruses might represent two distinct virus families. Taken together, the discovery of Odin retrotransposons narrowed down the evolutionary gaps between retrotransposons and canonical retroviruses and lokiretroviruses. IMPORTANCE The origin of retroviruses remains largely unclear. In this study, we discovered a novel retrotransposon lineage, Odin retrotransposons, within the genomes of sea anemones (order Actinaria). In contrast to retroviruses and most retrotransposons, Odin retrotransposons encode a dual RNase H domain but no env gene. Phylogenetic analyses showed that Odin retrotransposons were sisters to lokiretroviruses, and lokiretroviruses and Odin retrotransposons were sisters to retroviruses, establishing an evolutionary framework to decipher the origin of retroviruses (canonical retroviruses and lokiretroviruses). Our results provided insights into the diversity and deep evolution of LTR retrotransposons closely related to retroviruses.

Dataset Information

Loss of HSulf-1: The Missing Link between Autophagy and Lipid Droplets in Ovarian Cancer.

Publications

Loss of HSulf-1: The Missing Link between Autophagy and Lipid Droplets in Ovarian Cancer.

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