Similar Datasets
Project description:Stable overexpression of MED19 in androgen-dependent LNCaP cells promotes growth under conditions of androgen deprivation
| PRJNA676106 | ENA
Project description:We report the application of ChIP and RNA sequencing to identify the mechanism whereby stable overexpression of MED19 in androgen-dependent LNCaP cells promotes growth under conditions of androgen deprivation. We determined the MED19 and AR transcriptomes and cistromes in control and MED19 LNCaP cells. We also examined genome-wide H3K27 acetylation in both the absence and presence of androgens. We found that MED19 overexpression selectively alters AR occupancy, H3K27 acetylation, and gene expression. Under conditions of androgen deprivation, genes regulated by MED19 correspond to genes regulated by ELK1, a transcription factor that binds the AR N-terminus to induce select AR target gene expression and proliferation. This study provides important insight into the mechanisms of prostate cancer cell growth under low androgen, and underscores the importance of the MED19 in this process.
2021-01-20 | GSE161170 | GEO
Project description:We report the application of RNA sequencing to uncover the process through which sustained overexpression of the canonical MED19 isoform in androgen-dependent LNCaP cells enhances growth under conditions of androgen deprivation. We identified the canonical MED19 transcriptome by comparing control LNCaP cells with those expressing canonical MED19. This research offers significant understanding of the mechanism by which prostate cancer cells grow under low androgen conditions, emphasizing the key role of the canonical MED19 isoform in this process.
2023-07-06 | GSE236441 | GEO
Project description:We report the application of ChIP and RNA sequencing to identify the mechanism whereby stable overexpression of MED19 in androgen-dependent LNCaP cells promotes growth under conditions of androgen deprivation. We determined the MED19 and AR transcriptomes and cistromes in control and MED19 LNCaP cells. We also examined genome-wide H3K27 acetylation in both the absence and presence of androgens. We found that MED19 overexpression selectively alters AR occupancy, H3K27 acetylation, and gene expression. Under conditions of androgen deprivation, genes regulated by MED19 correspond to genes regulated by ELK1, a transcription factor that binds the AR N-terminus to induce select AR target gene expression and proliferation. This study provides important insight into the mechanisms of prostate cancer cell growth under low androgen, and underscores the importance of the MED19 in this process.
2021-01-20 | GSE161167 | GEO
Project description:MED19, a component of the mediator complex and a co-regulator of the androgen receptor (AR), is pivotal in prostate cancer cell proliferation. MED19 has two isoforms: a full-length "canonical" and a shorter "alternative" variant. Specific antibodies were developed to investigate these isoforms. Both exhibit similar expression in normal prostate development and adult prostate tissue, but the canonical isoform is elevated in prostate adenocarcinomas. Overexpression of canonical MED19 in LNCaP cells promotes growth under conditions of androgen deprivation in vitro and in vivo, mirroring earlier findings with alternative MED19-overexpressing LNCaP cells. Interestingly, alternative MED19 cells displayed strong colony formation in clonogenic assays under conditions of androgen deprivation, while canonical MED19 cells did not, suggesting distinct functional roles. These isoforms also modulated gene expression differently. Canonical MED19 triggered genes related to extracellular matrix remodeling while suppressing those involved in androgen-inactivating glucuronidation. In contrast, alternative MED19 elevated genes tied to cell movement and reduced those associated with cell adhesion and differentiation. The ratio of MED19 isoform expression in prostate cancers shifts with the disease stage. Early-stage cancers exhibit higher canonical MED19 expression than alternative MED19, consistent with canonical MED19's ability to promote cell proliferation under androgen deprivation. Conversely, alternative MED19 levels were higher in later-stage metastatic prostate cancer than in canonical MED19, reflecting alternative MED19's capability to enhance cell migration and autonomous cell growth. Our findings suggest that MED19 isoforms play unique roles in prostate cancer progression and highlights MED19 as a potential therapeutic target for both early and late-stage prostate cancer.
| S-EPMC10600210 | biostudies-literature
Project description:Androgen deprivation therapy (ADT) is a mainstay of prostate cancer treatment, given the dependence of prostate cells on androgen and the androgen receptor (AR). However, tumors become ADT-resistant, and there is a need to understand the mechanism. One possible mechanism is the upregulation of AR co-regulators, although only a handful have been definitively linked to disease. We previously identified the Mediator subunit MED19 as an AR co-regulator, and reported that MED19 depletion inhibits AR transcriptional activity and growth of androgen-insensitive LNCaP-abl cells. Therefore, we proposed that MED19 upregulation would promote AR activity and drive androgen-independent growth. Here, we show that stable overexpression of MED19 in androgen-dependent LNCaP cells promotes growth under conditions of androgen deprivation. To delineate the mechanism, we determined the MED19 and AR transcriptomes and cistromes in control and MED19-overexpressing LNCaP cells. We also examined genome-wide H3K27 acetylation. MED19 overexpression selectively alters AR occupancy, H3K27 acetylation, and gene expression. Under conditions of androgen deprivation, genes regulated by MED19 correspond to genes regulated by ELK1, a transcription factor that binds the AR N-terminus to induce select AR target gene expression and proliferation, and genomic sites occupied by MED19 and AR are enriched for motifs associated with ELK1. Strikingly, MED19 upregulates expression of monoamine oxidase A (MAOA), a factor that promotes prostate cancer growth. MAOA depletion reduces androgen-independent growth. MED19 and AR occupy the MAOA promoter, with MED19 overexpression enhancing AR occupancy and H3K27 acetylation. Furthermore, MED19 overexpression increases ELK1 occupancy at the MAOA promoter, and ELK1 depletion reduces MAOA expression and androgen-independent growth. This suggests that MED19 cooperates with ELK1 to regulate AR occupancy and H3K27 acetylation at MAOA, upregulating its expression and driving androgen independence in prostate cancer cells. This study provides important insight into the mechanisms of prostate cancer cell growth under low androgen, and underscores the importance of the MED19-MAOA axis in this process.
| S-EPMC7875385 | biostudies-literature
Project description:BackgroundAndrogen signaling plays a critical role in the development of prostate cancer and its progression. However, androgen-independent prostate cancer cells emerge after hormone ablation therapy, resulting in significant clinical problems. We have previously demonstrated that the HOXB13 homeodomain protein functions as a prostate cancer cell growth suppressor by inhibiting androgen-mediated signals. However, the role of the HOXB13 in androgen-independent growth of prostate cancer cells remains unexplained.ResultsIn this report, we first demonstrated that HOXB13 was highly overexpressed in hormone-refractory tumors compared to tumors without prostate-specific antigen after initial treatment. Functionally, in an androgen-free environment minimal induction of HOXB13 in LNCaP prostate cancer cells, to the level of the normal prostate, markedly promoted cell proliferation while suppression inhibited cell proliferation. The HOXB13-mediated cell growth promotion in the absence of androgen, appears to be mainly accomplished through the activation of RB-E2F signaling by inhibiting the expression of the p21waf tumor suppressor. Indeed, forced expression of HOXB13 dramatically decreased expression of p21waf; this inhibition largely affected HOXB13-mediated promotion of E2F signaling.ConclusionsTaken together, the results of this study demonstrated the presence of a novel pathway that helps understand androgen-independent survival of prostate cancer cells. These findings suggest that upregulation of HOXB13 is associated with an additive growth advantage of prostate cancer cells in the absence of or low androgen concentrations, by the regulation of p21-mediated E2F signaling.
| S-EPMC2890607 | biostudies-literature
Project description:Transcriptome profiles of alternative MED19 LNCaP and control LNCaP cells cultured under androgen deprivation with vehicle or R1881
| PRJNA676100 | ENA
Project description:The androgen receptor (AR) acts as a ligand-dependent transcription factor, whereas mutant AR lacking the C-terminal ligand-binding domain functions in a ligand-independent manner. In the present study we report that the C-terminal truncated AR, which we named AR-NH1 (the N-terminal fragment of AR cleaved in the neighborhood of helix 1 of the ligand-binding domain), is produced in LNCaP prostatic carcinoma cells. The AR-NH1 of ~90 kDa was observed in an androgen-independent LNCaP subline and was further accumulated by the proteasome inhibitor MG132. MG132 treatment caused the accumulation of AR-NH1 even in parent LNCaP cells. AR-NH1 was produced in the absence of ligand or in the presence of the AR antagonist bicalutamide, whereas AR agonists suppressed its production. AR-NH1 was detected with different AR antibodies recognizing amino acid residues 1-20 and 300-316 and was also generated from exogenous AR. Both siRNA-mediated AR knockdown and treatment with a serine protease inhibitor (4-(2-aminoethyl)-benzenesulfonyl fluoride) reduced AR-NH1 levels. According to the predicted cleavage site (between amino acid residues 660-685) and its nuclear localization, it is assumed that AR-NH1 functions as a constitutively active transcription factor. These data suggest that AR-NH1 is produced under hormone therapy and contributes to the development of castration-resistant prostate cancer due to its ligand-independent transcriptional activity.
| S-EPMC7685070 | biostudies-literature
Project description:Transcriptome profiles of canonical MED19 LNCaP and control LNCaP cells cultured under androgen deprivation with vehicle or R1881 treatment
| PRJNA990811 | ENA