A novel role for the SUMO E3 ligase PIAS1 in cancer metastasis

Dadakhujaev, Shorafidinkhuja; Salazar-Arcila, Carolina; Netherton, Stuart J.; Chandhoke, Amrita Singh; Singla, Arvind K.; Jirik, Frank R.; Bonni, Shirin

doi:10.18632/oncoscience.27

Cited by 29 publications

(55 citation statements)

References 38 publications

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“…PIAS1 is also thought to be a critical regulator in the epithelial mesenchymal transition (EMT) [41]. It has been reported that the expression of PIAS1 regulates the TGFβ-induced metastasis of breast cancer with PIAS1 as a possible biomarker for metastasis in breast cancer [42]. Our data shows that either form of NR causes an up regulation of PIAS1 in the proteomic and gene expression data and SUMOylation in the gene ontology report.…”

Section: Discussionsupporting

confidence: 52%

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Nutrient restriction of glucose or serum results in similar proteomic expression changes in 3D colon cancer cell cultures

et al. 2016

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Nutrient restriction, also known as caloric restriction, has been extensively examined for its positive impact on lifespan, immune system boost, and aging. In addition, nutrient restriction is implicated in decreasing cancer initiation and progression. Given the phenotypic changes associated with nutrient restriction, we hypothesized significant protein expression alterations must be associated with caloric restriction. To compare the molecular and phenotypic changes caused by glucose restriction and fetal bovine serum (FBS) restriction there is need for an efficient model system. We establish three dimensional cell culture models, known as spheroids, in the HCT 116 colorectal cancer cell line as a high throughput model for studying the proteomic changes associated with nutrient restriction. Flow cytometry was used to assess apoptosis and autophagy levels in the spheroids under nutrient restriction. Isobaric tags for relative and absolute quantification (iTRAQ) and liquid chromatography tandem mass spectrometry were used to determine differential protein abundances between the nutrient restriction conditions. We identified specific proteins that have implications in cancer progression and metastasis that are differentially regulated by restriction of either glucose or serum. These proteins include the up regulation of sirtuin 1 (SIRT1) and protein inhibitor of activated STAT 1 (PIAS1) and down regulation of multi-drug resistance protein (MRP1) and Zinc finger and BTB domain-containing protein 7A (ZBTB7). The results indicate nutrient restriction causes lower apoptotic and higher autophagy rates in HCT 116 spheroids. In addition, proteins shown to be differentially regulated by both glucose and serum restriction were similarly regulated.

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Section: Discussionsupporting

confidence: 52%

“…A protein is SUMOylated by covalent conjugation of small ubiquitin-like modifier (SUMO) protein, through the use of E1, E2, and E3 ligase enzymes, to lysine residues of the target protein [42],[43]. The function of PIAS1 is as an E3-type SUMO ligase.…”

Section: Discussionmentioning

confidence: 99%

Nutrient restriction of glucose or serum results in similar proteomic expression changes in 3D colon cancer cell cultures

et al. 2016

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“…For in vivo sumoylation assays, cells were lysed in TNTE (50 mM Tris, 150 mM NaCl, and 1 mM EDTA) buffer containing 0.5% Triton X-100 along with protease and phosphatase inhibitors, and 0.1% SDS. 69,73,76 In addition, 20 mM NEM isopeptidase inhibitor was included in the lysis buffer where indicated. 45,65 Cell extracts were collected in 1.75 ml Eppendorf tubes and centrifuged at 14 000 × g for 10 min at 4°C.…”

Section: Methodsmentioning

confidence: 99%

The ubiquitin ligase Smurf2 suppresses TGFβ-induced epithelial–mesenchymal transition in a sumoylation-regulated manner

Karve

Dadakhujaev

et al. 2015

Cell Death Differ

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Epithelial-mesenchymal transition (EMT) is a fundamental cellular process in epithelial tissue development, and can be reactivated in cancer contributing to tumor invasiveness and metastasis. The cytokine transforming growth factor-β (TGFβ) is a key inducer of EMT, but the mechanisms that regulate TGFβ-induced EMT remain incompletely understood. Here, we report that knockdown of the ubiquitin ligase Smurf2 promotes the ability of TGFβ to induce EMT in a three-dimensional cell culture model of NMuMG mammary epithelial cells. In other studies, we identify Smurf2 as a target of the small ubiquitin like modifier (SUMO) pathway. We find that the SUMO-E2 conjugating enzyme Ubc9 and the SUMO E3 ligase PIAS3 associate with Smurf2 and promote its sumoylation at the distinct sites of Lysines 26 and 369. The sumoylation of Smurf2 enhances its ability to induce the degradation of the TGFβ receptor and thereby suppresses EMT in NMuMG cells. Collectively, our data reveal that Smurf2 acts in a sumoylationregulated manner to suppress TGFβ-induced EMT. These findings have significant implications for our understanding of epithelial tissue development and cancer. Cell Death and Differentiation (2016) 23, 876-888; doi:10.1038/cdd.2015; published online 18 December 2015Epithelial-mesenchymal transition (EMT) is an essential process in epithelial tissue morphogenesis in the developing organism and contributes to postnatal events including mammary postnatal gland development as well as wound healing.1,2 Importantly, EMT can be reactivated during cancer and may contribute to tumor invasiveness.3 Epithelial cells undergoing EMT change phenotypically from cuboidal to fibroblastic morphology, lose epithelial markers including E-cadherin, gain mesenchymal markers, and display increased cell motility and invasiveness. 4,5 The secreted factor transforming growth factor-β (TGFβ) has emerged as a potent inducer of EMT with key roles in development and cancer.6 Thus, there has been interest in the mechanisms that mediate TGFβ-induced EMT.Smurf2 (Smad (Sma and mad) ubiquitination regulatory factor-2) is a HECT (for homology to E6 carboxy terminus domain)-containing E3 ubiquitin ligase that specifies substrates for ubiquitination and degradation by the proteasome.7,8 Smurf2 regulates key biological processes during development and homeostasis including cell polarity, cell cycle, and senescence in an E3 ligase-dependent or -independent manner.9-15 The biological functions of Smurf2 occur via regulation of signaling pathways including the TGFβ-Smad signaling pathway. [16][17][18][19][20][21][22][23] However, the role of Smurf2 in TGFβ-induced EMT has remained to be determined.Sumoylation refers to the covalent attachment of the small ubiquitin-like modifier (SUMO), to protein substrates by the SUMO pathway.24 SUMO is linked to its substrates by an iso-peptide bond between C-terminal carboxyl group of SUMO and ε-amino group of a lysine residue in the substrate. The SUMO E2 conjugating enzyme Ubc9, the second enzyme of a three-step catalytic cascade...

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“…Moreover, SUMOylation and PIAS1 have shown to play a key role in the transcriptional maintenance of basal breast cancer phenotype (Bogachek et al, 2014). Evidence for a role of the PIAS1 in suppression of TGF-b-induced activation of matrix metalloproteinase MMP2 in breast cancer cells has been also reported (Dadakhujaev et al, 2014). However, there is no genomewide information of the role that PIAS1 plays in the regulation of AR target genes in breast cancer cells.…”

Section: Introductionmentioning

confidence: 99%

Androgen receptor- and PIAS1-regulated gene programs in molecular apocrine breast cancer cells

Malinen

Toropainen

Jääskeläinen

et al. 2015

Molecular and Cellular Endocrinology

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A novel role for the SUMO E3 ligase PIAS1 in cancer metastasis

Cited by 29 publications

References 38 publications

Nutrient restriction of glucose or serum results in similar proteomic expression changes in 3D colon cancer cell cultures

Nutrient restriction of glucose or serum results in similar proteomic expression changes in 3D colon cancer cell cultures

The ubiquitin ligase Smurf2 suppresses TGFβ-induced epithelial–mesenchymal transition in a sumoylation-regulated manner

Androgen receptor- and PIAS1-regulated gene programs in molecular apocrine breast cancer cells

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