RNAseq of WFU3 mouse prostate epithelial stem cells with knockdown of Map3k7, Chd1, and both
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE132664 | GEO | 2019/07/01
REPOSITORIES: GEO
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Project description:Purpose: The goal of this study is to identify transcriptome-wide changes that occur in a human prostate cell line with knockdown of MAP3K7(TAK1) and CHD1, in the presence and absence of androgens. We utilize this cell line as a model of an aggressive prostate cancer subtype consisting of deletions of both MAP3K7 and CHD1 in human patients. RNAseq comparing shControl, shMAP3K7(TAK1), shCHD1, and both (shMAP3K7/shCHD1) was used to identify transcriptome changes resulting from loss of each of these genes, as well as their effects on androgen signaling. Abstract of associated study: Prostate cancer (PCa) genomic subtypes that stratify aggressive disease and inform treatment decisions at the primary stage are currently limited. Previously, we functionally validated an aggressive subtype present in 15% of PCa characterized by dual deletion of MAP3K7 and CHD1. Recent studies in the field have focused on deletion of CHD1 and its role in androgen receptor (AR) chromatin distribution and resistance to AR-targeted therapy, however, CHD1 is rarely lost without co-deletion of MAP3K7. Here we show that in the clinically relevant context of co-loss of MAP3K7 and CHD1 there are significant, collective changes to aspects of AR signaling. While CHD1 loss mainly impacts the expansion of the AR cistrome, loss of MAP3K7 drives increased AR target gene expression. PCa cell line models engineered to co-suppress MAP3K7 and CHD1 also demonstrated increased AR-v7 expression and resistance to the AR-targeting drug enzalutamide. Furthermore, we determined that low protein expression of both genes is significantly associated with biochemical recurrence (BCR) in a clinical cohort of radical prostatectomy specimens. Low MAP3K7 expression, however, was the strongest independent predictor for risk of BCR over all other tested clinicopathologic factors including CHD1 expression. Collectively, these findings illustrate the importance of MAP3K7 loss in a molecular subtype of PCa that poses challenges to conventional therapeutic approaches.
2021-04-12 | GSE168663 | GEO
Project description:Purpose: The goal of this study is to identify genome-wide changes in AR chromatin binding that occur in a human prostate cell line with knockdown of MAP3K7(TAK1) and CHD1, in the presence and absence of androgens. We utilize this cell line as a model of an aggressive prostate cancer subtype consisting of deletions of both MAP3K7 and CHD1 in human patients. ChIP-seq comparing AR chromatin binding in shControl, shMAP3K7(TAK1), shCHD1, and both (shMAP3K7/shCHD1) was used to identify AR cistrome changes resulting from loss of each of these genes. Abstract of associated study: Prostate cancer (PCa) genomic subtypes that stratify aggressive disease and inform treatment decisions at the primary stage are currently limited. Previously, we functionally validated an aggressive subtype present in 15% of PCa characterized by dual deletion of MAP3K7 and CHD1. Recent studies in the field have focused on deletion of CHD1 and its role in androgen receptor (AR) chromatin distribution and resistance to AR-targeted therapy, however, CHD1 is rarely lost without co-deletion of MAP3K7. Here we show that in the clinically relevant context of co-loss of MAP3K7 and CHD1 there are significant, collective changes to aspects of AR signaling. While CHD1 loss mainly impacts the expansion of the AR cistrome, loss of MAP3K7 drives increased AR target gene expression. PCa cell line models engineered to co-suppress MAP3K7 and CHD1 also demonstrated increased AR-v7 expression and resistance to the AR-targeting drug enzalutamide. Furthermore, we determined that low protein expression of both genes is significantly associated with biochemical recurrence (BCR) in a clinical cohort of radical prostatectomy specimens. Low MAP3K7 expression, however, was the strongest independent predictor for risk of BCR over all other tested clinicopathologic factors including CHD1 expression. Collectively, these findings illustrate the importance of MAP3K7 loss in a molecular subtype of PCa that poses challenges to conventional therapeutic approaches.
2021-04-12 | GSE168651 | GEO
Project description:Purpose: The goal of this study is to identify transcriptome-wide changes that occur in a human prostate cell line with knockdown of MAP3K7(TAK1) and CHD1, in the presence and absence of androgens. We utilize this cell line as a model of an aggressive prostate cancer subtype consisting of deletions of both MAP3K7 and CHD1 in human patients. RNAseq comparing shControl and shMAP3K7/shCHD1 was used to identify transcriptome changes resulting from loss of these genes, as well as their effects on androgen signaling. Abstract of associated study: Prostate cancer (PCa) genomic subtypes that stratify aggressive disease and inform treatment decisions at the primary stage are currently limited. Previously, we functionally validated an aggressive subtype present in 15% of PCa characterized by dual deletion of MAP3K7 and CHD1. Recent studies in the field have focused on deletion of CHD1 and its role in androgen receptor (AR) chromatin distribution and resistance to AR-targeted therapy, however, CHD1 is rarely lost without co-deletion of MAP3K7. Here we show that in the clinically relevant context of co-loss of MAP3K7 and CHD1 there are significant, collective changes to aspects of AR signaling. While CHD1 loss mainly impacts the expansion of the AR cistrome, loss of MAP3K7 drives increased AR target gene expression. PCa cell line models engineered to co-suppress MAP3K7 and CHD1 also demonstrated increased AR-v7 expression and resistance to the AR-targeting drug enzalutamide. Furthermore, we determined that low protein expression of both genes is significantly associated with biochemical recurrence (BCR) in a clinical cohort of radical prostatectomy specimens. Low MAP3K7 expression, however, was the strongest independent predictor for risk of BCR over all other tested clinicopathologic factors including CHD1 expression. Collectively, these findings illustrate the importance of MAP3K7 loss in a molecular subtype of PCa that poses challenges to conventional therapeutic approaches.
2021-04-12 | GSE168670 | GEO
Project description:Purpose: The goal of this study is to identify transcriptome-wide changes that occur in a human prostate cell line with knockdown of MAP3K7(TAK1) and CHD1, in the presence and absence of androgens. We utilize this cell line as a model of an aggressive prostate cancer subtype consisting of deletions of both MAP3K7 and CHD1 in human patients. RNAseq comparing shControl and shMAP3K7/shCHD1 was used to identify transcriptome changes resulting from loss of these genes, as well as their effects on androgen signaling. Abstract of associated study: Prostate cancer (PCa) genomic subtypes that stratify aggressive disease and inform treatment decisions at the primary stage are currently limited. Previously, we functionally validated an aggressive subtype present in 15% of PCa characterized by dual deletion of MAP3K7 and CHD1. Recent studies in the field have focused on deletion of CHD1 and its role in androgen receptor (AR) chromatin distribution and resistance to AR-targeted therapy, however, CHD1 is rarely lost without co-deletion of MAP3K7. Here we show that in the clinically relevant context of co-loss of MAP3K7 and CHD1 there are significant, collective changes to aspects of AR signaling. While CHD1 loss mainly impacts the expansion of the AR cistrome, loss of MAP3K7 drives increased AR target gene expression. PCa cell line models engineered to co-suppress MAP3K7 and CHD1 also demonstrated increased AR-v7 expression and resistance to the AR-targeting drug enzalutamide. Furthermore, we determined that low protein expression of both genes is significantly associated with biochemical recurrence (BCR) in a clinical cohort of radical prostatectomy specimens. Low MAP3K7 expression, however, was the strongest independent predictor for risk of BCR over all other tested clinicopathologic factors including CHD1 expression. Collectively, these findings illustrate the importance of MAP3K7 loss in a molecular subtype of PCa that poses challenges to conventional therapeutic approaches.
2021-04-12 | GSE168665 | GEO
Project description:A key principle of oncolytic viral therapy is that many cancers develop defects in their antiviral responses, making them more susceptible to virus infection. However, some cancers display resistance to viral infection. Many of these resistant cancers constitutively express interferon-stimulated genes (ISGs). The goal of these experiments was to determine the role of two tumor suppressor genes, MAP3K7 and CHD1, in viral resistance and ISG expression in PC3 prostate cancer cells resistant to oncolytic vesicular stomatitis virus (VSV). MAP3K7 and CHD1 are often co-deleted in aggressive prostate cancers. Silencing expression of MAP3K7 and CHD1 in PC3 cells increased susceptibility to M protein mutant M51R-VSV as shown by increased expression of viral genes, increased yield of progeny virus, and reduction of tumor growth in nude mice. Silencing MAP3K7 alone had a greater effect on virus susceptibility than silencing CHD1. Silencing MAP3K7 and CHD1 decreased constitutive expression of ISG mRNAs and proteins, whereas silencing MAP3K7 alone decreased expression of ISG proteins, but actually increased expression of ISG mRNAs. These results suggest a role for the protein product of MAP3K7, transforming growth factor β-activated kinase 1 (TAK1), in regulating translation of ISG mRNAs and a role of CHD1 in maintaining the transcription of ISGs.
2021-02-24 | GSE145937 | GEO
Project description:We previously reported that human T cell lymphotropic virus 1 (HTLV-1) Tax oncoprotein constitutively activates TAK1. Here, we established Tax-positive HuT-102 cells stably downregulated TAK1 expression by short-hairpin RNA (HuT-shTAK1 cells), and investigated the physiological function of TAK1. Microarray analysis demonstrated that several interferon (IFN)-inducible genes including chemokines such as CXCL10 and CCL5 were significantly downregulated in HuT-shTAK1 cells. In contrast, Tax-mediated constitutive activation of NF-kB was intact in HuT-shTAK1 cells. IRF3, a critical transcription factor in innate immunity to viral infection, was constitutively activated in a Tax-dependent manner. Activation of IRF3 and IRF3-dependent gene expression were dependent on TAK1 and TBK1. On the other hand, IRF4, another IRF family of transcription factor overexpressed in a Tax-independent manner, negatively regulated the TAK1-dependent IRF3 transcriptional activity. Together, HTLV-1 manipulates IFN signaling by regulating both positive and negative IRFs. HuT-102 cells, a human cutaneous T cell lymphoma, were stably transfected with shRNA expression vectors against human MAP3K7 (TAK1) or firefly luciferase (Luc). The cells were maintained in media containing 0.5 mg/ml G418. For the experiment, the cells were incubated in media without G418 for 36 h at 37M-BM-0C. Total RNA samples were prepared from the cells. Gene expression was analyzed by an Affymetrix GeneChipM-BM-. system with a Human Genome U133-plus 2.0 array for analysis of over 47,000 transcripts. Sample preparation for array hybridization was carried out as described in the manufacturerM-bM-^@M-^Ys instructions. Two replicates per sample type.
2009-08-18 | E-GEOD-16219 | biostudies-arrayexpress
Project description:Homeostatic control of dendritic cell (DC) survival is crucial for a productive adaptive immune response, but the molecular mechanism is not well defined. Moreover, how DCs influence homeostasis of the immune system under steady state remains unclear. Combining DC-specific and inducible deletion systems, we report here that the kinase TAK1 is an essential regulator of DC survival and immune system homeostasis and function. Deficiency of TAK1 in CD11c+ cells diminished DC populations, especially the CD8+ and CD103+ DC subsets in the lymphoid and non-lymphoid organs, respectively. This was associated with increased apoptosis of DCs, whereas DC proliferation and differentiation from precursors appeared largely normal. In addition, acute deletion of TAK1 caused DC apoptosis, indicating a direct role of TAK1 in actively maintaining DC survival. TAK1 deficiency impaired activities of the pro-survival NF-kB and AKT pathways but upregulated expression of the pro-apoptotic molecule Bim. Under steady state, loss of TAK1 in DCs resulted in a myeloid proliferative disorder, and altered homeostasis of T cells. In response to antigen stimulation, TAK1-deficient DCs were impaired for T cell priming and regulatory T cell generation. Therefore, TAK1 orchestrates a pro-survival checkpoint in DCs that affects the homeostasis and function of the immune system RNA extracted from three replicate samples of wild-type and Map3k7 (TAK1) knockout dendritic cells was analyzed on Affymetrix gene expression arrays
2012-01-23 | E-GEOD-34417 | biostudies-arrayexpress
Project description:RNA-Seq of 22RV1 human prostate cancer cells with knockdown of MAP3K7 and CHD1
| PRJNA713360 | ENA
Project description:RNA-Seq of LAPC4 human prostate cancer cells with knockdown of MAP3K7 and CHD1
| PRJNA713351 | ENA
Project description:Deregulation of chromatin architecture is emerging as a critical feature of carcinogenesis, and genomic alterations in nucleosome remodelers are common in human cancer. Recurrent deletion of the chromatin remodeler CHD1 is among the most common alterations in prostate cancer, but its role as a tumor suppressor and the reasons for the tissue-specific nature of CHD1 deletion remain undefined. Here, we show that deletion of CHD1 drives prostate tumorigenesis and fundamentally reprograms the transcriptional program of the androgen receptor (AR), diverting AR towards an oncogenic transcriptional program and away from a growth suppressive transcriptome. Conditional deletion of Chd1 in mouse prostate resulted in prostate neoplasia in vivo, confirming CHD1 as a tumor suppressor in prostate tissue. In prostate cells, the interactome of chromatin-bound CHD1 was enriched for factors that regulate nuclear receptor function, and interrogation of the CHD1 cistrome revealed promoter-independent enrichment of CHD1 at sites specifically occupied by AR and its associated transcriptional regulators. Deletion of CHD1 resulted in a dramatic redistribution of AR across the genome, localizing AR to sites enriched for HOXB13, and depleting AR at AR-halfsite motifs, consistent with the AR cistrome and epigenetic marks in human prostate cancer samples. Furthermore, the CHD1 null AR cistrome was associated with a unique AR transcriptional signature, enriched for pro-oncogenic pathways and depleted for processe consistent with normal prostatic function. Collectively, these data implicate CHD1 as a prostate-specific tumor suppressor which constrains the oncogenic functions of AR though maintenance of a normal AR transcriptional program.
2019-07-18 | GSE117430 | GEO