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GSE90922
Homo sapiens
9 Downloadable Samples
Affymetrix Human Genome U133 Plus 2.0 Array (hgu133plus2)
Description
Our previous study using nude rats revealed that the parental JDCaP xenografts predominantly expressed full-length androgen receptor (AR) whereas the relapsed JDCaP xenografts after castration acquired AR splice variants including AR-V7 and ARv567es. To understand molecular mechanisms underlying the acquisition of AR splice variants in the JDCaP model, we performed microarray analysis using RNA samples of the xenografts without castration (Parent), the relapsed xenografts overexpressing full-length AR and AR-V7 (ARhiV7hi), and the relapsed xenografts expressing ARv567es (ARv567es).
Publication Title
The RNA helicase DDX39B and its paralog DDX39A regulate androgen receptor splice variant AR-V7 generation.
Sample Metadata Fields
Specimen part
View Samples- Homo sapiens
- 14 Downloadable Samples
- Affymetrix Human Gene 1.0 ST Array (hugene10st)
Description
C-C chemokine ligand 2 (CCL2) plays pivotal roles in tumor formation, progression, and metastasis. Although CCL2 expression has been found to be dependent on the nuclear factor (NF)B signaling pathway, the regulation of CCL2 production in tumor cells has remained unclear. We have identified a noncanonical pathway for regulation of CCL2 production that is mediated by mammalian target of rapamycin complex 1 (mTORC1) but independent of NF-B. Multiple phosphoproteomics approaches identified the transcription factor forkhead box K1 (FOXK1) as a downstream target of mTORC1. Activation of mTORC1 induces dephosphorylation of FOXK1 resulting in transactivation of the CCL2 gene. Inhibition of the mTORC1-FOXK1 axis attenuated insulin-induced CCL2 production as well as the accumulation of tumor-associated monocytes-macrophages and tumor progression in mice. Our results suggest that FOXK1 directly links mTORC1 signaling and CCL2 expression in a manner independent of NF-B, and that CCL2 produced by this pathway contributes to tumor progression.
Publication Title
Noncanonical Pathway for Regulation of CCL2 Expression by an mTORC1-FOXK1 Axis Promotes Recruitment of Tumor-Associated Macrophages.
Sample Metadata Fields
Cell line
View Samples- Homo sapiens
- 10 Downloadable Samples
- Affymetrix Human Gene 1.0 ST Array (hugene10st)
Description
C-C chemokine ligand 2 (CCL2) plays pivotal roles in tumor formation, progression, and metastasis. Although CCL2 expression has been found to be dependent on the nuclear factor (NF)B signaling pathway, the regulation of CCL2 production in tumor cells has remained unclear. We have identified a noncanonical pathway for regulation of CCL2 production that is mediated by mammalian target of rapamycin complex 1 (mTORC1) but independent of NF-B. Multiple phosphoproteomics approaches identified the transcription factor forkhead box K1 (FOXK1) as a downstream target of mTORC1. Activation of mTORC1 induces dephosphorylation of FOXK1 resulting in transactivation of the CCL2 gene. Inhibition of the mTORC1-FOXK1 axis attenuated insulin-induced CCL2 production as well as the accumulation of tumor-associated monocytes-macrophages and tumor progression in mice. Our results suggest that FOXK1 directly links mTORC1 signaling and CCL2 expression in a manner independent of NF-B, and that CCL2 produced by this pathway contributes to tumor progression.
Publication Title
Noncanonical Pathway for Regulation of CCL2 Expression by an mTORC1-FOXK1 Axis Promotes Recruitment of Tumor-Associated Macrophages.
Sample Metadata Fields
Cell line
View Samples- Homo sapiens
- 4 Downloadable Samples
- Affymetrix Human Gene 1.0 ST Array (hugene10st)
Description
C-C chemokine ligand 2 (CCL2) plays pivotal roles in tumor formation, progression, and metastasis. Although CCL2 expression has been found to be dependent on the nuclear factor (NF)B signaling pathway, the regulation of CCL2 production in tumor cells has remained unclear. We have identified a noncanonical pathway for regulation of CCL2 production that is mediated by mammalian target of rapamycin complex 1 (mTORC1) but independent of NF-B. Multiple phosphoproteomics approaches identified the transcription factor forkhead box K1 (FOXK1) as a downstream target of mTORC1. Activation of mTORC1 induces dephosphorylation of FOXK1 resulting in transactivation of the CCL2 gene. Inhibition of the mTORC1-FOXK1 axis attenuated insulin-induced CCL2 production as well as the accumulation of tumor-associated monocytes-macrophages and tumor progression in mice. Our results suggest that FOXK1 directly links mTORC1 signaling and CCL2 expression in a manner independent of NF-B, and that CCL2 produced by this pathway contributes to tumor progression.
Publication Title
Noncanonical Pathway for Regulation of CCL2 Expression by an mTORC1-FOXK1 Axis Promotes Recruitment of Tumor-Associated Macrophages.
Sample Metadata Fields
Cell line
View Samples- Homo sapiens
- 5 Downloadable Samples
- Affymetrix Human Gene 2.0 ST Array (hugene20st)
Description
Adoptive T cell therapy (ACT) is a promising therapeutic approach for cancer patients. The use of allogeneic T cell grafts will improve its applicability and versatility provided that inherent allogeneic responses are controlled. T cell activation is finely regulated by multiple signaling molecules that are transcriptionally controlled by epigenetic mechanisms. Through extensive chemical probe screening, we found that inhibiting DOT1L, a histone H3-lysine 79 methyltransferase, alleviated allogeneic T cell responses.
Publication Title
DOT1L inhibition attenuates graft-versus-host disease by allogeneic T cells in adoptive immunotherapy models.
Sample Metadata Fields
Specimen part, Subject
View Samples- Homo sapiens
- 6 Downloadable Samples
Illumina HiSeq 2500
Description
Adoptive T cell therapy (ACT) is a promising therapeutic approach for cancer patients. The use of allogeneic T cell grafts will improve its applicability and versatility provided that inherent allogeneic responses are controlled. Through extensive chemical probe screening, we found that inhibiting DOT1L, a histone H3-lysine 79 methyltransferase, alleviated allogeneic T cell responses. DOT1L inhibition with SGC0946 selectively ameliorated low-avidity T cell responses but not high-avidity antitumor T cell responses mediated by the high-affinity T cell receptor or chimeric antigen receptor. The inhibition of DOT1L in T cells prevented the development of graft-versus-host disease while retaining potent antitumor activity in xenogeneic ACT models. These results suggest that DOT1L inhibition may enable the safe and effective use of allogeneic antitumor T cells by suppressing unwanted immunological reactions in ACT. Overall design: To investigate how DOT1L inhibition modulates the T cell activation signal, we compared gene expression profiles between SGC0946-treated or DMSO-treated (control) T cells by RNA-sequencing analysis. Human CD8+ T cells derived from three different healthy donors were cultured in the presence of SGC0946 or DMSO. Total RNA was collected from each sample and gene expression profiles were analyzed by RNA-sequencing using an Illumina HiSeq 2500 sequencer.
Publication Title
DOT1L inhibition attenuates graft-versus-host disease by allogeneic T cells in adoptive immunotherapy models.
Sample Metadata Fields
Specimen part, Treatment, Subject
View Samples- Mus musculus
- 8 Downloadable Samples
- Affymetrix Mouse Genome 430 2.0 Array (mouse4302)
Description
Global DNA hypomethylation and DNA hypermethylation of promoter regionsincluding tumor suppressor genesare frequently detected in human cancers. Although many studies have suggested a contribution to carcinogenesis, it is still unclear whether the aberrant DNA hypomethylation observed in tumors is a consequence or a cause of cancer. We found that overexpression of Stella (also known as PGC7, Dppa3), a maternal factor required for the maintenance of DNA methylation in early embryos, induced global DNA hypomethylation and transformation in NIH3T3 cells. This hypomethylation was due to the binding of Stella to Np95 (also known as Uhrf1, ICBP90) and the subsequent impairment of Dnmt1 localization. In addition, enforced expression of Stella enhanced the metastatic ability of B16 melanoma cells through the induction of metastasis-related genes by inducing DNA hypomethylation of their promoter regions. Such DNA hypomethylation itself causes cellular transformation and metastatic ability. These data provide new insight into the function of global DNA hypomethylation in carcinogenesis.
Publication Title
Global DNA hypomethylation coupled to cellular transformation and metastatic ability.
Sample Metadata Fields
Cell line
View Samples- Rattus norvegicus
- 18 Downloadable Samples
- Affymetrix Rat Genome 230 2.0 Array (rat2302)
Description
It is well-known that indomethacin (the cyclooxygenase 1 & 2 inhibitor) and RU486 (or mifepristone, the progesterone receptor antagonist) block follicular rupture in rats. To characterize genetic alterations in unruptured follicles, gene expression profiles in ovarian follicle were analyzed in indomethacin- and RU486-treated female Sprague-Dawley rats. Ovaries are collected at 22:00 on the proestrus day and 10:00 on the following estrus day after a single dose of indomethacin and RU486. Histopathologically, changes depicting responses to LH surge were observed in ovaries, uteri and vagina. Total RNA was extracted from pre-ovulatory follicles or unruptured follicles collected by laser microdissection and analyzed by GeneChip. Among genes showing statistically significant changes compared to control groups, following changes were considered relevant to induction of unruptured follicles. In indomethacin-treated rats, Wnt4 was down-regulated, suggesting effect on tissue integrity and steroid genesis. In RU486-treated rats, Adamts1, Adamts9, Edn2, Ednra, Lyve1, Plat, and Pparg were down-regulated. These changes suggest effects on proteolysis for extracellular matrix or surrounding tissue (Adamts1 & 9, and Plat), constriction of smooth muscle surrounding follicles (Edn2, Ednra, and Pparg), follicular fluid (Lyve1), and angiogenesis (Pparg). Down-regulation of angiogenesis related genes (Angpt2, Hmox1, and Vegfa) was observed in both treatment groups. Here, we clarify genetic alterations induced by the inhibition of cyclooxygenase or progesterone receptor.
Publication Title
Altered gene expression profile in ovarian follicle in rats treated with indomethacin and RU486.
Sample Metadata Fields
Specimen part, Treatment
View Samples- Homo sapiens
- 5 Downloadable Samples
- Affymetrix Human Genome U133 Plus 2.0 Array (hgu133plus2)
Description
Metabolism is tightly coupled with the process of aging, and tumorigenesis. However, the mechanisms regulating metabolic properties in different contexts remain unclear. Cellular senescence is widely recognized as an important tumor suppressor function and accompanies metabolic remodeling characterized by increased mitochondrial oxidative phosphorylation (OXPHOS). Here we showed retinoblastoma (RB) is required for the increased OXPHOS in oncogene-induced senescent (OIS) cells. Combined metabolic and gene expression profiling revealed that RB mediated activation of the glycolytic pathway in OIS cells, causing upregulation of several glycolytic genes and concomitant increases in the levels of associated metabolites in the glycolytic pathway. Knockdown of these genes by small interfering RNAs (siRNAs) resulted in decreased mitochondrial respiration, suggesting that RB-mediated glycolytic gene activation promotes metabolic flux into the OXPHOS pathway. These results suggest that coordinate transcriptional activation of metabolic genes by RB enables OIS cells to maintain metabolically bivalent states that both glycolysis and OXPHOS are highly active. Collectively, our findings demonstrated a previously unrecognized function of RB in OIS cells.
Publication Title
Retinoblastoma protein promotes oxidative phosphorylation through upregulation of glycolytic genes in oncogene-induced senescent cells.
Sample Metadata Fields
Cell line, Treatment
View Samples- Homo sapiens
- 3 Downloadable Samples
- Affymetrix Human Genome U133 Plus 2.0 Array (hgu133plus2)
Description
By transcriptome analysis of IMR-90 human fibroblasts following oncogene-induced senescence (OIS) and replicative senescence (RS), we identified commonly regulated genes in both conditions.
Publication Title
The SETD8/PR-Set7 Methyltransferase Functions as a Barrier to Prevent Senescence-Associated Metabolic Remodeling.
Sample Metadata Fields
Cell line, Treatment
View Samples