Siah2 control on tumor environment
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA555115 | ENA |
REPOSITORIES: ENA
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Project description:Understanding mechanisms underlying anti-tumor immunity is pivotal for improving immune-based cancer therapies. Here we demonstrate that growth of inoculated BRAF mutant melanoma cells was inhibited in Siah2-/- mice, up to a complete loss. Melanoma grown in Siah2-/- mice exhibited increased proinflammatory immune components, signified by enhanced intra-tumoral activated T cells, along with decreased expression of Ccl17 and Ccl22, and decreased Foxp3 expression. A marked reduction in Treg proliferation was associated with inhibition of Treg cell cycle progression. Correspondingly, G1 cell cycle arrest in Siah2-/- Tregs coincided with elevated expression of the cyclin dependent kinase inhibitor p27, a Siah2 substrate. Growth of PD1-unresponsive melanoma was effectively inhibited up to complete tumor rejection in Siah2-/- mice subjected to PD1 blockade, highlighting synergy between PD1 inhibition and Siah2 loss. Siah2 regulation of Treg recruitment and cell cycle progression effectively controls melanoma development and confers synthetic lethality when combined with anti-PD1 therapy.
2019-07-18 | GSE134412 | GEO
Project description:Siah2 control of T-regulatory cells limits anti-tumor immunity
| PRJNA556492 | ENA
Project description:Siah2 control of T-regulatory cells limits anti-tumor immunity
| PRJNA554787 | ENA
Project description:Understanding mechanisms underlying anti-tumor immunity is pivotal for improving immune-based cancer therapies. Here we demonstrate that growth of inoculated BRAF-mutant melanoma cells was inhibited, up to complete loss, in Siah2-/- mice.
2019-11-27 | GSE134814 | GEO
Project description:Gene expression profiling was performed to identify Siah2-dependent changes in cells subjected to ER stress, hypoxia, and combined glucose/oxygen deprivation. To establish the magnitude of the Siah2 effect on the ER stress response, we have compared gene expression profiles of WT and Siah1a-/-::Siah2-/- mouse embryo fibroblasts (MEFs) that were subjected to glycosylation inhibitor tunicamycin (TM), thapsigargin (TG), glucose deprivation, or glucose/oxygen deprivation. Overall, this analysis confirmed changes associated with ER stress that had not previously been associated with Siah2 signaling, substantiating Siah2 as a key coordinator of ER stress through the ATF4 and sXbp1 pathways. WT and Siah1a/Siah2 KO MEF cells were treated with TM or TG for 6 h, or subjected for 12 h to oxygen deprivation, glucose deprivation or a combination of oxygen and glucose deprivation, in duplicate.
2014-04-01 | E-GEOD-39244 | biostudies-arrayexpress
Project description:Gene expression profiling was performed to identify Siah2-dependent changes in cells subjected to ER stress, hypoxia, and combined glucose/oxygen deprivation. To establish the magnitude of the Siah2 effect on the ER stress response, we have compared gene expression profiles of WT and Siah1a-/-::Siah2-/- mouse embryo fibroblasts (MEFs) that were subjected to glycosylation inhibitor tunicamycin (TM), thapsigargin (TG), glucose deprivation, or glucose/oxygen deprivation. Overall, this analysis confirmed changes associated with ER stress that had not previously been associated with Siah2 signaling, substantiating Siah2 as a key coordinator of ER stress through the ATF4 and sXbp1 pathways.
2014-04-01 | GSE39244 | GEO
Project description:The androgen receptor (AR) plays a central role in the development of castration resistant prostate cancer (CRPC). Here, we demonstrate that the ubiquitin ligase Siah2 targets a select pool of NCOR1-bound, transcriptionally inactive AR for ubiquitination dependent degradation, thereby promoting the expression of ~13% of AR target genes. The Siah2 binding sites located within the AR ligand-binding domain are mutated in PCa, resulting in attenuation of Siah2-mediated regulation. Siah2 is required for growth of PCa cells under androgen-deprivation conditions in vitro and in vivo. Significantly, inhibition of Siah2 promotes PCa regression upon castration and Siah2 expression is markedly increased in human CRPCs. Collectively our findings identify a key role for Siah2 in CRPC through the selective regulation of AR transcriptional activity. Tumor Harvest. When tumor size reached approximately 1.5 cm in diameter (6-8 weeks after injection), and the serum PSA was greater than 50 ng/ml, animals were surgically castrated under methoxyfluorane anesthesia and monitored for PSA levels for several weeks. Animals were sacrificed by carbon dioxide asphyxiation when tumors were harvested at several points along the PSA curve (pre-castrate (11), regressing (6), nadir (10), recurring (6) and castration resistant (12). Tumor segments were placed in RNALater (Qiagen) and frozen immediately at -80M-BM-0C.weeks. Tumors were harvested at several points along the PSA curve. The epithelial:stromal ratio is consistent within this tumor model and varies 10% between tumors, as assessed by immunohistochemistry of cytokeratin 14 (epithelium) and vimentin (stroma).
2013-02-15 | E-GEOD-44319 | biostudies-arrayexpress
Project description:Analysis of gene expression altered upon knockdown of Siah2 in prosate cancer cells. The objective is to elucidate which signaling pathways or transcription factors are regulated by the E3 ubiquitin ligase Siah2 in human prostate cancer cells. CWR22Rv1 cells were in fected with pLKO.1 control or Siah2 shRNA, and selected with 1ug/ml of puromycin to get stable transfectants. Total RNA was extracted for micorarray analysis to compare the diffentially expressed genes between pLKO.1 control and Siah2 knockdown cells.
2013-03-19 | E-GEOD-38851 | biostudies-arrayexpress
Project description:Chronic, low-grade adipose tissue inflammation associated with adipocyte hypertrophy is an important link in the relationship between obesity and insulin resistance. Although ubiquitin ligases are essential regulators of inflammatory processes, the role of these enzymes in metabolically driven adipose tissue inflammation is relatively unexplored. In this study, we found that the ubiquitin ligase Siah2 is a central factor in obesity-related adipose tissue inflammation. When challenged with chronic excess energy intake, Siah2-null mice become obese with enlarged adipocytes, but do not develop obesity-induced insulin resistance. Proinflammatory gene expression is substantially reduced in the Siah2-null epididymal adipose tissue of the obese Siah2KO mice.
2015-09-29 | GSE61839 | GEO
Project description:The androgen receptor (AR) plays a central role in the development of castration resistant prostate cancer (CRPC). Here, we demonstrate that the ubiquitin ligase Siah2 targets a select pool of NCOR1-bound, transcriptionally inactive AR for ubiquitination dependent degradation, thereby promoting the expression of ~13% of AR target genes. The Siah2 binding sites located within the AR ligand-binding domain are mutated in PCa, resulting in attenuation of Siah2-mediated regulation. Siah2 is required for growth of PCa cells under androgen-deprivation conditions in vitro and in vivo. Significantly, inhibition of Siah2 promotes PCa regression upon castration and Siah2 expression is markedly increased in human CRPCs. Collectively our findings identify a key role for Siah2 in CRPC through the selective regulation of AR transcriptional activity.
2013-02-15 | GSE44319 | GEO