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Effect of cajanin stilbene acid and its synthetic derivatives on MCF-7 breast cancer cells

ABSTRACT: Cajanin stilbene acid (CSA) was previously shown to induce cytotoxicity against cancer cells. We have employed microarray gene expression profiling to identify deregulated genes in MCF-7 breast cancer cells upon treatment with CSA and its synthetic derivatives (CSA6, CSA9, CSA19). TGM2 gene encoding transglutaminase 2 was commonly deregulated after treatment with all four CSA compounds. All compounds revealed strong effects on cell cycle progression and DNA damage response. Promoter motif analysis of the deregulated genes further supported the microarray results emphasizing the relevance of transcription factors regulating cell cycle and proliferation, MYC being among the most pronounced ones. Interestingly, cellular movement was among the top five affected cellular functions after treatment with the four derivatives.

ORGANISM(S): Homo sapiens

PROVIDER: GSE64430 | GEO | 2015/02/27

SECONDARY ACCESSION(S): PRJNA271005

REPOSITORIES: GEO

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Effect of cajanin stilbene acid and its synthetic derivatives on MCF-7 breast cancer cells

Project description:Cajanin stilbene acid (CSA) was previously shown to induce cytotoxicity against cancer cells. We have employed microarray gene expression profiling to identify deregulated genes in MCF-7 breast cancer cells upon treatment with CSA and its synthetic derivatives (CSA6, CSA9, CSA19). TGM2 gene encoding transglutaminase 2 was commonly deregulated after treatment with all four CSA compounds. All compounds revealed strong effects on cell cycle progression and DNA damage response. Promoter motif analysis of the deregulated genes further supported the microarray results emphasizing the relevance of transcription factors regulating cell cycle and proliferation, MYC being among the most pronounced ones. Interestingly, cellular movement was among the top five affected cellular functions after treatment with the four derivatives. Gene expression profiling study with Whole Human Genome RNA chips (8M-CM-^W60K Agilent) was performed in MCF-7 breast cancer cells upon treatment with CSA and its synthetic derivatives (CSA6, CSA9, CSA19). Twelve chips were used; control (x2), CSA (x2), control (x2), CSA6 (x2), CSA9 (x2), CSA19 (x2). MCF-7 cells were treated with the compounds (IC50 concentrations) for 72 hours or left untreated (DMSO control). Two independent experiments were performed for each treatment.

2015-02-27 | E-GEOD-64430 | biostudies-arrayexpress

Transcription profiling of sputum samples from individuals exercise-induced bronchoconstriction (EIB).

Project description:Asthma is a heterogeneous disease. Exercise-induced bronchoconstriction (EIB) is a distinct syndrome that occurs in 30-50% of asthmatics and is characterized by high levels of pro-inflammatory eicosanoids. We identified genes differentially expressed in the airways of asthmatics with EIB relative to asthmatics without EIB. Genes related to epithelial repair and mast cell infiltration including beta-tryptase and carboxypeptidase A3 were upregulated by exercise challenge in the asthma group with EIB. We confirmed that two novel mediators trefoil factor 3 (TFF3) and transglutaminase 2 (TGM2) have increased expression in airways cells and secreted product in the airways. In vitro studies indicate that 1) TFF3 induces nitric oxide synthase in airway epithelial cells from asthmatics and 2) TGM2 augments the enzymatic activity of secreted phospholipase A2 (sPLA2) group X, an enzyme recently been implicated in asthma pathogenesis. Since PLA2 serves as the first rate-limiting step leading to eicosanoid generation, these results suggest that TGM2 may be a key initiator of the airway inflammatory cascade in asthma. EIB positive and EIB negative subjects sampled pre- and post-exercise

2010-11-10 | E-GEOD-13785 | biostudies-arrayexpress

TGM2-Mediated Histone Transglutamination is Dictated by Steric Accessibility

Project description:Histone monoaminylation is a new class of chromatin post-translational modification whereby glutamines are transamidated by tissue transglutaminase 2 (TGM2). Initial studies of these marks have identified serotonylation and dopaminylation on H3Q5, suggesting the modification is a marker of active chromatin. However, little work has been conducted to understand the regulation of TGM2-mediated monoaminylation of chromatin. Here, we employed a highly sensitive TGM2 assay using the small molecule biotin-cadaverine as an acyl-acceptor substrate. In doing so, we discovered that, in addition to H3Q5, H3Q19 and H2A.ZQ123 and Q124 are glutaminyl substrates for TGM2 in vitro. Modification of these residues occurs in a sequence independent manner, with the primary determining factor for substrate selectivity being steric accessibility. We demonstrated that moving substrate glutamines near the histone fold domain turns them into non-substrates. Furthermore, we found that steric accessibility of glutamines appears to be controlled by higher order chromatin structures. Using nucleosome arrays as substrates, we successfully showed that formation of chromatin fibers in vitro reduces levels of monoaminylation. We then successfully extended these findings to a cell based system, showing that TGM2 is not enriched in heterochromatin and that H3Q5 serotonylation and H3K9me3 are mutually exclusive marks. In total, our results strongly suggest that TGM2, and monoaminylation, are excluded from heterochromatin based on steric accessibility

2022-10-05 | GSE198978 | GEO

Aberrant expression of transglutaminase 2 in pancreas and thymus of NOD mice underscores the importance of deamidation in neoantigen generation.

Project description:Post-translational modifications can lead to a break in immune tolerance in autoimmune diseases such as type 1 diabetes (T1D). Deamidation, the conversion of glutamine to glutamic acid by transglutaminase (TGM) enzymes, is a post-translational modification of interest, with deamidated peptides being reported as autoantigens in T1D. However, little is known about how Tgm2, the most ubiquitously expressed Tgm isoform, is regulated and how tolerance against deamidated peptides is lost. Here, we report on the aberrant expression and regulation of Tgm2, in the pancreas and thymus of NOD mice. We demonstrate that Tgm2 expression is induced by the inflammatory cytokines IL1β and IFNγ in a synergistic manner and that murine pancreatic islets of NOD mice have higher Tgm2 levels, while Tgm2 levels in thymic mTECs are reduced. We thus provide the first direct evidence to our knowledge that central tolerance establishment against deamidated peptides might be impaired due to lower Tgm2 expression in NOD mice, which together with the aberrantly high levels of deamidated peptides in NOD β-cells underscores the role of deamidation in amplifying T-cell reactivity.

2022-07-21 | PXD034102 | Pride

Hypoxia-mediated stabilization of HIF1A in prostatic intraepithelial neoplasia promotes cell plasticity and malignant progression

Project description:Prostate cancer (PCa) is a leading cause of cancer-related deaths. The slow evolution of precancerous lesions to malignant tumors provides a broad time-frame for preventing PCa. To characterize prostatic intraepithelial neoplasia (PIN) progression, we conducted longitudinal studies on Pten(i)pe-/- mice which recapitulate prostate carcinogenesis in humans. We discovered that early PINs are hypoxic and that hypoxia-inducible factor 1 alpha (HIF1A) signaling is activated in luminal cells, which enhances malignant progression. Luminal HIF1A dampens immune surveillance and drives luminal plasticity leading to the emergence of cells with selective Transglutaminase 2 (TGM2) expression and impaired androgen signaling. Importantly, elevated TGM2 levels in PCa patients are associated with shortened progression-free survival after prostatectomy. Finally, we show that pharmacologically inhibiting HIF1A impairs cell proliferation and induces apoptosis in PINs. Therefore, our study demonstrates that HIF1A is a target for PCa prevention, and that TGM2 is a promising prognostic biomarker of early relapse after prostatectomy.

2022-06-07 | GSE189784 | GEO

Histone monoaminylation dynamics are regulated by a single enzyme and promote neural rhythmicity

Project description:Histone H3 monoaminylations at glutamine(Q) 5 represent important epigenetic markers in neurons that play critical roles in the mediation of permissive gene expression. We previously demonstrated that H3Q5 serotonylation(ser) and dopaminylation(dop) are catalyzed by the Transglutaminase 2 (TGM2) enzyme. Here, we identified a new class of histone monoaminylation, H3Q5 histaminylation(his), which displayed dynamic diurnal expression in brain and contributed to neural rhythmicity. We found that H3Q5his, unlike H3Q5ser, electrostatically inhibited recruitment of the “reader” protein WDR5 and attenuated MLL1 methyltransferase activity on H3 lysine(K) 4. We determined that H3Q5 monoaminylation dynamics are dictated by local monoamine concentrations, which are sensed by TGM2. This noncanonical mechanism indicated that histone monoaminylations can be established and removed by a single enzyme based upon its sensing of cellular microenvironments.

2022-12-06 | GSE209834 | GEO

Novel mediators of eicosanoid and epithelial nitric oxide production in asthma

2010-11-10 | GSE13785 | GEO

Essential role for CD30-Transglutaminase 2 axis in memory Th1 and Th17 cell generation.

Project description:Memory helper T (Th) cells are crucial for secondary immune responses against infectious microorganisms but also drive the pathogenesis of chronic inflammatory diseases. Therefore, it is of fundamental importance to understand how memory T cells are generated. However, the molecular mechanisms governing memory Th cell generation remain incompletely understood. Here, we identified CD30 as a molecule heterogeneously expressed on effector Th1 and Th17 cells, and CD30hi effector Th1 and Th17 cells preferentially generated memory Th1 and Th17 cells. We found that CD30 mediated signal induced Transglutaminase-2 (TG2) expression, and that the TG2 expression in effector Th cells is essential for memory Th cell generation. In fact, Cd30-deficiency resulted in the impaired generation of memory Th1 and Th17 cells, which can be rescued by overexpression of TG2. Furthermore, transglutaminase-2 (Tgm2)-deficient CD4 T cells failed to become memory Th cells. As a result, T cells from Tgm2-deficient mice displayed impaired antigen-specific antibody production and attenuated Th17-mediated allergic responses. Our data indicate that CD30-induced TG2 expression in effector Th cells is essential for the generation of memory Th1 and Th17 cells, and that CD30 can be a marker for precursors of memory Th1 and Th17 cells.

2020-05-28 | GSE151301 | GEO

Essential role for CD30-Transglutaminase 2 axis in memory Th1 and Th17 cell generation.

2020-06-04 | GSE151691 | GEO

Cyclosporin A inhibits prostate cancer growth through suppression of E2F8

Project description:Cyclosporin A (CsA) is a potent immunosuppressive agent used clinically in organ transplantation. In this study, we examined that CsA exerts anti-tumor activity against prostate cancer. We performed microarray experiments to investigate the effect of CsA on the transcriptome of prostate cancer cells. CsA potently induced transcriptome change and primarily affected cell cycle-related gene signatures. These results suggest that CsA can be used as a potential therapeutic agent or an intriguing tool for exploring prostate cancer biology and identifying novel therapeutic targets.

2023-10-04 | GSE109505 | GEO

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