Ilicicolin-A exert antitumor effect in CRPCa via suppressing EZH2 signaling pathway
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA754394 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR15443833.fastq.gz | Fastqsanger.gz | |||
| SRR15443834.fastq.gz | Fastqsanger.gz | |||
| SRR15443835.fastq.gz | Fastqsanger.gz |
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Project description:Enhancer of zeste homolog 2 (EZH2) has critical roles in prostate cancer (PCa) progression and drug-resistance, which remains an obstacle for PCa treatment. Enzalutamide (ENZ) is a second-generation androgen receptor (AR) antagonist employed for treatment of metastatic castration-resistant prostate cancer (mCRPCa). A considerable proportion of tumors eventually develop resistance during treatment. Thus, agents that can overcome resistance to PCa are needed urgently. Ilicicolinal A (Ili-A), an ascochlorin derivative isolated from the coral-derived fungus Acremonium sclerotigenum GXIMD 02501, shows activity in human PCa cells, but its mechanism of action against CRPCa is not known. Here, RNA-sequencing showed the EZH2 pathway to be involved in PCa proliferation. Ili-A at low doses inhibited the transcriptional activity of EZH2 and AR targets by changing their protein expression. Interestingly, Ili-A suppressed the binding of EZH2 to promoter regions in AR/serine/threonine polo-like kinase-1/aurora kinase A. Moreover, low-dose Ili-A showed a synergistic effect with enzalutamide to inhibit survival of CRPCa cells in vitro, and enhanced the anti-cancer effect of enzalutamide on CRPCa xenografts with minimal side-effects. These data suggest that Ili-A could be used in combination with enzalutamide to treat CRPCa.
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Project description:Two PUFA, docosahexaenoic (DHA, 22: 6n3) and arachidonic acids (ARA, 20: 4n6), as well as their derivatives such as eicosanoids, regulate different activities, which include changes in receptor signaling, the composition of rafts, cell metabolism, and membrane structures. These also modify the function of transcription factors and their target genes, a key step essential for the function of FA-activated signaling. This work is focused to determine the antitumor actions of these compounds linked to the regulation of gene transcription on HT-29 colorectal cancer. For this, we performed antiproliferative antitumour assay, LDH breakage test, caspase-3 production, and proteome changes were assessed by SWATH-MS quantitative proteomics followed by pathway analysis in order to find out which molecular mechanisms were being affected. In all cases tested, DHA exercised antitumor actions to a higher extent than ARA, acting mainly by means of down-regulating most of the proteasome system particles, while ARA presented a heavy effect on all the six DNA replication helicase particles but did not affect proteasome. The results indicated that both DHA and ARA stopped colorectal cancer growth and proliferation, thus they represent the ideal candidates as chemopreventive agents.
2022-01-28 | PXD008653 | Pride
Project description:The Polycomb protein enhancer of zeste homolog 2 (EZH2) has critical roles in prostate cancer (PCa) progression and drug-resistance, which remains an obstacle for PCa treatment. Enzalutamide (ENZ) is a second-generation androgen receptor antagonist employed for treatment of metastatic castration-resistant prostate cancer A considerable proportion of tumors eventually develop resistance during treatment. Thus, agents that can overcome resistance to PCa are needed urgently. Ilicicolin A (Ili-A), an ascochlorin derivative isolated from the coral-derived fungus Acremonium sclerotigenum GXIMD 02501, shows antiproliferative activity in human PCa cells, but its mechanism of action against Castration-resistant prostate cancer is not known. Herein, RNA-sequencing showed the EZH2 pathway to be involved in PCa proliferation. Ili-A at low doses reduced the protein level of EZH2, leading to transcriptional change. Interestingly, Ili-A suppressed the binding of EZH2 to promoter regions in AR/serine/threonine polo-like kinase-1/aurora kinase A. Moreover, Ili-A could enhance the anticancer activity of enzalutamide in CRPC cancer models. These data suggest that Ili-A could be used in combination with enzalutamide to treat CRPC.
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Project description:Overexpression of EZH2 in estrogen receptor negative (ER-) breast cancer promotes metastasis. EZH2 has been mainly studied as the catalytic component of the Polycomb Repressive Complex 2 (PRC2) that mediates gene repression by trimethylating histone H3 at lysine 27 (H3K27me3). However, how EZH2 drives metastasis despite the low H3K27me3 levels observed in ER- breast cancer is unknown. We have shown that in human invasive carcinomas and distant metastases, cytoplasmic EZH2 phosphorylated at T367 is significantly associated with ER- disease and low H3K27me3 levels. Here, we explore the interactome of EZH2 and of a phosphodeficient mutant EZH2_T367A. We identified novel interactors of EZH2, and identified interactions that are dependent on the phosphorylation and cellular localization of EZH2 that may play a role in EZH2 dependent metastatic progression.
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Project description:To date there are very few tools to reverse the induced dedifferentiation program in CRPC and to improve the response to the androgen deprivation therapy. Here we report that MAT2A is an important oncogenic cofactor of ERG/EZH2 transcriptional reprogramming impacting significantly the androgenic pathway. Using RNA sequencing coupled with ATAC, here we reveal an important link between ERG/MAT2A and EZH2 that impact on AR signaling pathway. This aberrant epigenetic program can be reversed by MAT2A inhibition which establish a near physiologic AR transcriptional program. Targeting MAT2A alone or in combination with EZH2 inhibitors reverse stemness in multiple models including prostatospheres from human PDX and GEM models of aggressive prostate cancer. Targeting MAT2A enhance the sensitivity to the androgenic blockade by Enzalutamide and to EZH2 inhibitors
2023-07-15 | E-MTAB-12031 | biostudies-arrayexpress
Project description:To date there are very few tools to reverse the induced dedifferentiation program in CRPC and to improve the response to the androgen deprivation therapy. Here we report that MAT2A is an important oncogenic cofactor of ERG/EZH2 transcriptional reprogramming impacting significantly the androgenic pathway. Using RNA sequencing coupled with ATAC, here we reveal an important link between ERG/MAT2A and EZH2 that impact on AR signaling pathway. This aberrant epigenetic program can be reversed by MAT2A inhibition which establish a near physiologic AR transcriptional program. Targeting MAT2A alone or in combination with EZH2 inhibitors reverse stemness in multiple models including prostatospheres from human PDX and GEM models of aggressive prostate cancer. Targeting MAT2A enhance the sensitivity to the androgenic blockade by Enzalutamide and to EZH2 inhibitors
2023-07-15 | E-MTAB-12029 | biostudies-arrayexpress
Project description:To date there are very few tools to reverse the induced dedifferentiation program in CRPC and to improve the response to the androgen deprivation therapy. Here we report that MAT2A is an important oncogenic cofactor of ERG/EZH2 transcriptional reprogramming impacting significantly the androgenic pathway. Using RNA sequencing coupled with ATAC, here we reveal an important link between ERG/MAT2A and EZH2 that impact on AR signaling pathway. This aberrant epigenetic program can be reversed by MAT2A inhibition which establish a near physiologic AR transcriptional program. Targeting MAT2A alone or in combination with EZH2 inhibitors reverse stemness in multiple models including prostatospheres from human PDX and GEM models of aggressive prostate cancer. Targeting MAT2A enhance the sensitivity to the androgenic blockade by Enzalutamide and to EZH2 inhibitors.
2023-08-07 | E-MTAB-12536 | biostudies-arrayexpress
Project description:To date there are very few tools to reverse the induced dedifferentiation program in CRPC and to improve the response to the androgen deprivation therapy. Here we report that MAT2A is an important oncogenic cofactor of ERG/EZH2 transcriptional reprogramming impacting significantly the androgenic pathway. Using RNA sequencing coupled with ATAC, here we reveal an important link between ERG/MAT2A and EZH2 that impact on AR signaling pathway. This aberrant epigenetic program can be reversed by MAT2A inhibition which establish a near physiologic AR transcriptional program. Targeting MAT2A alone or in combination with EZH2 inhibitors reverse stemness in multiple models including prostatospheres from human PDX and GEM models of aggressive prostate cancer. Targeting MAT2A enhance the sensitivity to the androgenic blockade by Enzalutamide and to EZH2 inhibitors.
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Project description:In this study, using ChIP sequencing, we identified EZH2 target genes in two prognostic subgroups of chronic lymphocytic leukemia with distinct outcome, i.e. IGHV-unmutated/subset #1 and IGHV-mutated/subset #4. Our data identified many oncogenic pathways enriched equally by EZH2 target genes in both prognostic subgroups. Importantly, we identified PI3K pathway as differentially enriched pathway by EZH2 between the two prognostic sub groups. Validation of EZH2 target genes for EZH2 occupancy on selected PI3K pathway target genes were performed using independent CLL patient samples and CLL cell lines using siRNA mediated down regulation and ChIP assays. In conclusion, for the first time we characterized EZH2 target genes in CLL to understand the role of EZH2 in regulating the oncogenic pathways for improved therapeutic intervention and designing better drugs for targeting EZH2 in CLL.
2019-06-24 | GSE115772 | GEO
Project description:To date there are very few tools to reverse the induced dedifferentiation program in CRPC and to improve the response to the androgen deprivation therapy. Here we report that MAT2A is an important oncogenic cofactor of ERG/EZH2 transcriptional reprogramming impacting significantly the androgenic pathway. Using RNA sequencing coupled with ATAC, here we reveal an important link between ERG/MAT2A and EZH2 that impact on AR signaling pathway. This aberrant epigenetic program can be reversed by MAT2A inhibition which establish a near physiologic AR transcriptional program. Targeting MAT2A alone or in combination with EZH2 inhibitors reverse stemness in multiple models including prostatospheres from human PDX and GEM models of aggressive prostate cancer. Targeting MAT2A enhance the sensitivity to the androgenic blockade by Enzalutamide and to EZH2 inhibitors
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