ONECUT2 inhibition by chemical compound treatment in 22Rv1
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE97548 | GEO | 2018/10/26
REPOSITORIES: GEO
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Project description:Purpose: Tumor heterogeneity complicates patient treatment and can be due to transitioning of cancer cells across phenotypic cell states. This process is associated with the acquisition of independence from an oncogenic driver, such as the estrogen receptor (ER) in breast cancer (BC), resulting in tumor progression, therapeutic failure and metastatic spread. The transcription factor ONECUT2 (OC2) has been shown to be a master regulator protein of metastatic castration-resistant prostate cancer (mCRPC) tumors that promotes lineage plasticity to a drug-resistant neuroendocrine (NEPC) phenotype. Here, we investigate the role of OC2 in the dynamic conversion between different molecular subtypes in BC. Methods: We analyze OC2 expression and clinical significance in BC using public databases and immunohistochemical staining. In vitro, we perform RNA-Seq, RT-qPCR and western-blot after OC2 enforced expression. We also assess cellular effects of OC2 silencing and inhibition with a drug-like small molecule in vitro and in vivo. Results: OC2 is highly expressed in a substantial subset of hormone receptor negative human BC tumors and tamoxifen-resistant models, and is associated with poor clinical outcome, lymph node metastasis and heightened clinical stage. OC2 inhibits ER expression and activity, suppresses a gene expression program associated with luminal differentiation and activates a basal-like state at the gene expression level. We also show that OC2 is required for cell growth and survival in metastatic BC models and that it can be targeted with a small molecule inhibitor providing a novel therapeutic strategy for patients with OC2 active tumors. Conclusions: The transcription factor OC2 is a driver of BC heterogeneity and a potential drug target in distinct cell states within the breast tumors.
2024-05-23 | GSE242541 | GEO
Project description:Androgen receptor- (AR-) indifference is a mechanism of resistance to hormonal therapy in prostate cancer (PC). Here we demonstrate that ONECUT2 (OC2) activates resistance through multiple drivers associated with adenocarcinoma, stem-like and neuroendocrine (NE) variants. Direct OC2 gene targets include the glucocorticoid receptor (GR; NR3C1) and the NE splicing factor SRRM4, which are key drivers of lineage plasticity. Thus, OC2, despite its previously described NEPC driver function, can indirectly activate a portion of the AR cistrome through epigenetic activation of GR. Mechanisms by which OC2 regulates gene expression include promoter binding, enhancement of genome-wide chromatin accessibility, and super-enhancer reprogramming. Pharmacologic inhibition of OC2 suppresses lineage plasticity reprogramming induced by the AR signaling inhibitor enzalutamide. These results demonstrate that OC2 activation promotes a range of drug resistance mechanisms associated with treatment-emergent lineage variation in PC and support enhanced efforts to therapeutically target OC2 as a means of suppressing treatment-resistant disease.
2024-08-10 | PXD050634 | Pride
Project description:Tumor heterogeneity complicates patient treatment and can be due to transitioning of cancer cells across phenotypic cell states. This process is associated with the acquisition of independence from an oncogenic driver, such as the estrogen receptor (ER) in breast cancer, resulting in tumor progression, therapeutic failure and metastatic spread. Here we identify the transcription factor ONECUT2 (OC2) as a lineage plasticity regulator of breast cancer (BC) that suppresses the estrogen axis and promotes luminal to basal transition. OC2 is highly expressed in a substantial subset of hormone receptor negative human BC tumors and is associated with poor clinical outcome, lymph node metastasis and heightened clinical stage. We also show that OC2 is required for cell growth and survival in metastatic BC models and that it can be targeted with a small molecule inhibitor providing a novel therapeutic strategy for patients with OC2 active tumors.
2024-05-23 | GSE242540 | GEO
Project description:Tumor heterogeneity complicates patient treatment and can be due to transitioning of cancer cells across phenotypic cell states. This process is associated with the acquisition of independence from an oncogenic driver, such as the estrogen receptor (ER) in breast cancer, resulting in tumor progression, therapeutic failure and metastatic spread. Here we identify the transcription factor ONECUT2 (OC2) as a lineage plasticity regulator of breast cancer (BC) that suppresses the estrogen axis and promotes luminal to basal transition. OC2 is highly expressed in a substantial subset of hormone receptor negative human BC tumors and is associated with poor clinical outcome, lymph node metastasis and heightened clinical stage. We also show that OC2 is required for cell growth and survival in metastatic BC models and that it can be targeted with a small molecule inhibitor providing a novel therapeutic strategy for patients with OC2 active tumors.
2024-05-23 | GSE242539 | GEO
Project description:In order to determine whether ONECUT2 directly regulates the AR transcriptional program, or whether the effect of ONECUT2 is a mere consequence of AR downregulation, we performed ONECUT2 ChIP-sequencing (ChIP-seq) using the 22Rv1 human castration resistant prostate cancer cell line, which expresses high levels of ONECUT2 in comparison to other human prostate cancer cell lines
2018-10-26 | GSE97551 | GEO
Project description:Androgen receptor- (AR-) indifference is a mechanism of resistance to hormonal therapy in prostate cancer (PC). Here we demonstrate that the HOX/CUT transcription factor ONECUT2 (OC2) directly activates resistance through multiple drivers associated with adenocarcinoma, stem-like and neuroendocrine (NE) variants. OC2 regulates gene expression by promoter binding, enhancement of chromatin accessibility, and formation of novel super-enhancers. Pharmacologic inhibition of OC2 suppresses lineage plasticity reprogramming induced by the AR signaling inhibitor enzalutamide. These results demonstrate that OC2 activation promotes a range of drug resistance mechanisms associated with treatment-emergent lineage variation in PC.
2023-11-21 | GSE244022 | GEO
Project description:Androgen receptor- (AR-) indifference is a mechanism of resistance to hormonal therapy in prostate cancer (PC). Here we demonstrate that the HOX/CUT transcription factor ONECUT2 (OC2) directly activates resistance through multiple drivers associated with adenocarcinoma, stem-like and neuroendocrine (NE) variants. OC2 regulates gene expression by promoter binding, enhancement of chromatin accessibility, and formation of novel super-enhancers. Pharmacologic inhibition of OC2 suppresses lineage plasticity reprogramming induced by the AR signaling inhibitor enzalutamide. These results demonstrate that OC2 activation promotes a range of drug resistance mechanisms associated with treatment-emergent lineage variation in PC.
2023-11-21 | GSE244024 | GEO
Project description:Androgen receptor- (AR-) indifference is a mechanism of resistance to hormonal therapy in prostate cancer (PC). Here we demonstrate that the HOX/CUT transcription factor ONECUT2 (OC2) directly activates resistance through multiple drivers associated with adenocarcinoma, stem-like and neuroendocrine (NE) variants. OC2 regulates gene expression by promoter binding, enhancement of chromatin accessibility, and formation of novel super-enhancers. Pharmacologic inhibition of OC2 suppresses lineage plasticity reprogramming induced by the AR signaling inhibitor enzalutamide. These results demonstrate that OC2 activation promotes a range of drug resistance mechanisms associated with treatment-emergent lineage variation in PC.
2023-11-21 | GSE244023 | GEO
Project description:Purpose: Even in last stage of metastatic castration-resistant prostate cancer, androgen receptor (AR) signaling remains active.To derive high metastatic prostate cancer (PCa), we labeled AR-positive but castration-resistant 22Rv1 PCa cells with luciferase gene (22Rv1-Luc2) and these cells were orthotopically implanted in mouse prostate for spontaneous progression. Methods: 2 × 10^5 of luciferase-expressing 22Rv1 cells (22Rv1-Luc2) cells were implanted in the anterior prostate of nude mice. After 12-14 weeks, the host mice were necropsied and the metastases from lumbar lymph nodes and primary tumors were dissected under laminar flow. Tumor tissues were minced using sterile scalpels and further digested with Collagenase D for 1 h. The lymph node metastatic cancer cells, named 22Rv1-M1, were orthotopically reimplanted in nude mice. At 12 weeks, the secondary metastases were isolated in the lumbar lymph nodes and designated as 22Rv1-M2 cells. Suspension of 1 × 10^6 22Rv1-M2 cells in DPBS was injected into nude mice through the tail vein, and mice developed metastases (22Rv1-M3) after 6 week. This procedure was repeated once to attain the 22Rv1-M4. Results: 22Rv1-derived metastatic cell lines exhibit increased in vitro and in vivo invasion activity as the progression from 22Rv1 to M4. Transcriptomic analysis of genome-wide gene expression in the M4 tumors reveal the unique gene expression profile compared to 22Rv1 tumors. Conclusions: Transcriptomic data provide the gene network for decoding the mechanism of PCa metastasis.
2017-12-01 | GSE99857 | GEO
Project description:To determine the underlying mechanism of ONECUT2 in prostate cancer hypoxia, we conducted a series of RNA-Seq and ChIP-Seq experiments in LNCaP and PC3 cells under normoxia and hypoxia conditions. We did RNA-Seq in LNCaP cells with or without OC2 overexpression and in PC3 cells with or without OC2 knockdown. We used anti-Flag antibody to perform the ChIP-Seq experiment in PC3 cells with Flag and OC2 fusion protein overexpression. We also performed HIF1A ChIP-Seq in AR-negative prostate cancer cell line PC3 under hypoxia condition with or without ONECUT2 or SMAD3 siRNA knockdown. SMAD3 and HIF2A ChIP-Seq were conducted in PC3 cells under hypoxia condition. To confirm the interactions between transcription factors, we also performed ChIP-reChIP-seq. We did the primary ChIP experiment using anti-SMAD3 antibody and then we subjected the ChIPed chromatin by the primary ChIP to reChIP experiments using anti-HIF1A or anti-HIF2A antibody. The reChIPed DNA was submitted to next generation sequencing.
2019-02-27 | GSE106305 | GEO