ATF6 is required for the survival of castration-resistant prostate cancer cells
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE199026 | GEO | 2022/03/23
REPOSITORIES: GEO
Similar Datasets
Project description:The Unfolded Protein Response (UPR) maintains endoplasmic reticulum (ER) homeostasis and is essential for retinal health. Activating Transcription Factor 6 (ATF6) controls a key UPR branch and upregulates genes that mitigate ER stress. Small molecule modulators of ATF6 have been characterized in cell culture models that increase or decrease the amount of the cleaved, transcriptional activator domain of ATF6 generated from the full-length precursor. However, the effects of these small molecule ATF6 modulators remains unclear in vivo, in part because of the lack of antibodies that robustly detect the cleaved, activated form of ATF6 in model organisms like mice. Here, we used targeted RNA sequencing (RNA-seq) to assess the transcriptional response to intraocular delivery of Ceapin-A7 (an ATF6 inhibitor) and AA147 (an ATF6 activator) in the mouse retina. Using this strategy, we demonstrate that Ceapin-A7 significantly suppressed ATF6 transcriptional targets, whereas AA147 induced ATF6-regulated genes in retinal tissue of the eye. We also show that neither small molecule ATF6 modulator caused retinal cell death, compromised vision, or triggered ER stress by histology, functional testing, and transcriptional analysis. These results identify a transcriptional strategy to sensitively detect and quantify Ceapin-A7 and AA147 modulation of ATF6 in vivo. These findings also identify non-toxic conditions for further in vivo evaluation of small molecule ATF6 modulators in mouse vision loss disease models linked to ER stress.
2025-08-19 | GSE289701 | GEO
Project description:ATF6 encodes a transcription factor that is activated during the Unfolded Protein Response to protect cells from ER stress. Loss of ATF6α and its paralog ATF6β, results in embryonic lethality, notochord dysgenesis, and in people, loss of ATF6α specifically, results in malformed neuroretina and congenital vision loss. These phenotypes implicate an essential role for ATF6 during vertebrate development. We investigated the function of ATF6 in development using human stem cells undergoing differentiation into multipotent germ layers, nascent tissues, and organs. We artificially activated ATF6 in stem cells with a recently identified small molecule ATF6 agonist, and we inhibited ATF6 using iPSCs from patients harboring ATF6 mutations. We discovered that ATF6 suppresses pluripotency, enhances differentiation, and surprisingly, guides stem cells toward mesodermal cell fates. Our findings reveal a novel role for ATF6 during differentiation and identify a new strategy to robustly create mesodermal tissues through modulation of the ATF6 arm of the UPR.
2017-11-14 | GSE106847 | GEO
Project description:ATF6 is required for the survival of castration-resistant prostate cancer cells
| PRJNA818029 | ENA
Project description:Hepatocellular carcinoma (HCC) is the fastest growing cause of cancer-related mortality with limited therapies. While endoplasmic reticulum (ER)-stress and the unfolded protein response (UPR) are implicated in HCC, the involvement of the UPR-transducer activating transcription factor 6 alpha (ATF6α) remains unclear. We generated hepatocyte specific n-ATF6 overexpression transgenic mice via Cre-mediated recombination.
2024-12-28 | GSE285262 | GEO
Project description:Hepatocellular carcinoma (HCC) is the fastest growing cause of cancer-related mortality with limited therapies. While endoplasmic reticulum (ER)-stress and the unfolded protein response (UPR) are implicated in HCC, the involvement of the UPR-transducer activating transcription factor 6 alpha (ATF6α) remains unclear. In contrast to the well-characterized role of ATF6α-activation as an adaptive response to ER-stress, we here demonstrate its hitherto unknown function as an ER stress-inducing oncoprotein and metabolic master-regulator restricting cancer-immunosurveillance. In human HCC, ATF6α-activation significantly correlated with reduced patient-survival, tumor-progression, local immunosuppression, and higher recurrence rates of liver-cancer upon hepatectomy. Hepatocyte-specific ATF6α-activation in mice induced progressive hepatitis with ER-stress, immunosuppression, and hepatocyte-proliferation. Concomitantly, activated-ATF6α increased glycolysis and repressed gluconeogenic enzyme fructose-1,6-bisphosphatase 1 (FBP1). Restoring FBP1 expression prevented ATF6α-activation-related pathologies. Prolonged ATF6α-activation in hepatocytes triggered hepatocarcinogenesis, intratumoral T-cell infiltration, and nutrient-deprived immune-exhaustion. Immune-checkpoint blockade (ICB) efficiently restored immunosurveillance and dramatically reduced HCC. In line, HCC patients with a significantly higher ATF6α-activation signature presented complete response to ICB monotherapy. Targeting Atf6 via germline, hepatocyte-specific ablation, or therapeutic delivery of antisense-oligonucleotides dampened HCC in preclinical liver-cancer models. Thus, prolonged ATF6α-activation drives ER-stress, leading to aberrant glucose metabolism-dependent immunosuppression in liver cancer. Our findings propose persistently activated ATF6α as an oncoprotein, stratification-marker for liver-cancer ICB, and targetable therapeutic strategy against HCC.
2026-01-27 | PXD045903 | Pride
Project description:Hepatocellular carcinoma (HCC) is the fastest growing cause of cancer-related mortality with limited therapies. While endoplasmic reticulum (ER)-stress and the unfolded protein response (UPR) are implicated in HCC, the involvement of the UPR-transducer activating transcription factor 6 alpha (ATF6α) remains unclear. We generated hepatocyte specific n-ATF6 overexpression transgenic mice via Cre-mediated recombination. At 3 months age, livers from the transgenic mice and their wild type controls were harvested for ATAC-sequencing.
2024-12-28 | GSE285261 | GEO
Project description:Hepatocellular carcinoma (HCC) is the fastest growing cause of cancer-related mortality with limited therapies. While endoplasmic reticulum (ER)-stress and the unfolded protein response (UPR) are implicated in HCC, the involvement of the UPR-transducer activating transcription factor 6 alpha (ATF6α) remains unclear. We generated hepatocyte specific n-ATF6 overexpression transgenic mice via Cre-mediated recombination. At 3 months age, livers from the transgenic mice and their wild type controls were harvested for RNA isolation and followed with RNA-sequencing.
2025-11-05 | GSE244212 | GEO
Project description:Hepatocellular carcinoma (HCC) is the fastest growing cause of cancer-related mortality with limited therapies. While endoplasmic reticulum (ER)-stress and the unfolded protein response (UPR) are implicated in HCC, the involvement of the UPR-transducer activating transcription factor 6 alpha (ATF6α) remains unclear. We generated hepatocyte specific n-ATF6 overexpression transgenic mice via Cre-mediated recombination. At 6 months age, livers from the transgenic mice and their wild type controls were harvested for RNA isolation and followed with RNA-sequencing.
2025-11-05 | GSE244213 | GEO
Project description:Hepatocellular carcinoma (HCC) is the fastest growing cause of cancer-related mortality with limited therapies. While endoplasmic reticulum (ER)-stress and the unfolded protein response (UPR) are implicated in HCC, the involvement of the UPR-transducer activating transcription factor 6 alpha (ATF6α) remains unclear. In contrast to the well-characterized role of ATF6α-activation as an adaptive response to ER-stress, we here demonstrate its hitherto unknown function as an ER stress-inducing oncoprotein and metabolic master-regulator restricting cancer-immunosurveillance. In human HCC, ATF6α-activation significantly correlated with reduced patient-survival, tumor-progression, local immunosuppression, and higher recurrence rates of liver-cancer upon hepatectomy. Hepatocyte-specific ATF6α-activation in mice induced progressive hepatitis with ER-stress, immunosuppression, and hepatocyte-proliferation. Concomitantly, activated-ATF6α increased glycolysis and repressed gluconeogenic enzyme fructose-1,6-bisphosphatase 1 (FBP1). Restoring FBP1 expression prevented ATF6α-activation-related pathologies. Prolonged ATF6α-activation in hepatocytes triggered hepatocarcinogenesis, intratumoral T-cell infiltration, and nutrient-deprived immune-exhaustion. Immune-checkpoint blockade (ICB) efficiently restored immunosurveillance and dramatically reduced HCC. In line, HCC patients with a significantly higher ATF6α-activation signature presented complete response to ICB monotherapy. Targeting Atf6 via germline, hepatocyte-specific ablation, or therapeutic delivery of antisense-oligonucleotides dampened HCC in preclinical liver-cancer models. Thus, prolonged ATF6α-activation drives ER-stress, leading to aberrant glucose metabolism-dependent immunosuppression in liver cancer. Our findings propose persistently activated ATF6α as an oncoprotein, stratification-marker for liver-cancer ICB, and targetable therapeutic strategy against HCC.
2025-11-16 | GSE244343 | GEO
Project description:Mammalian ATF6α/β are membrane-bound transcription factors which are activated by endoplasmic reticulum (ER) stress-induced proteolysis to upregulate various ER quality control proteins to maintain the homeostasis of the ER. ATF6α- and ATF6β-single knockout mice develop normally but ATF6α/β-double knockout causes embryonic lethality, the reason for which remains unknown. Here, we showed that medaka fish exhibits the same phenotype regarding the effects of deleting ATF6α, ATF6β, and both. Analyses revealed that ER stress occurred physiologically during early embryonic development, particularly in the brain, otic vesicle and notochord. The absence of transcriptional induction of ER chaperones in ATF6α/β-double knockout blocked notochord development, which was partially rescued by microinjection-mediated overexpression of the major ER chaperone BiP. Thus, ATF6α/β-mediated adjustment of chaperones to the increased demands in the ER is essential for development of the notochord, which synthesizes and secretes large amounts of extracellular matrix proteins to serve as the body axis.
2013-02-20 | GSE37174 | GEO