EZH2-targeted PROTACs target the EZH2/FOXM1 axis and reduce breast cancer cell growth [CUT&Tag]
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1125359 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR29462286_1.fastq.gz | Fastqsanger.gz | |||
| SRR29462286_2.fastq.gz | Fastqsanger.gz | |||
| SRR29462287_1.fastq.gz | Fastqsanger.gz | |||
| SRR29462287_2.fastq.gz | Fastqsanger.gz | |||
| SRR29462288_1.fastq.gz | Fastqsanger.gz |
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Project description:Breast cancer (BCa) remains the second leading cause of cancer-related mortalities in women, and acquired resistance to hormone therapies, such as tamoxifen, an estrogen receptor inhibitor, is a major hurdle in the treatment of luminal BCa. Another subtype, triple negative BCa (TNBC), is associated with aggressive disease and poor prognosis. The enhancer of zeste homolog 2 (EZH2), the methyltransferase component of the polycomb repressive complex 2 (PRC2), is overexpressed in BCa and has been implicated in tamoxifen resistance. In addition to its PRC2-dependent canonical transcription repressive role through catalyzing histone 3 lysine 27 trimethylation (H3K27me3), evidence suggests that EZH2 can function noncanonically, in a methyltransferase-independent manner, as a transcription activator through interacting with hormone receptors and oncogenic transcription factors. Unlike methyltransferase inhibitors, proteolysis targeting chimeras (PROTAC), which target EZH2 and interacting proteins for degradation, can suppress both activating and repressive functions of EZH2. Previous studies have suggested that PROTACs can be leveraged to inhibit TNBC cell growth. In this study, we expand our scope to test whether EZH2 targeted PROTACs can effectively inhibit luminal BCa cell growth. We find that EZH2-targeted PROTACs, MS177 and MS8815, effectively inhibited the growth luminal BCa cells, including those with acquired tamoxifen resistance, to a much greater degree when compared to methyltransferase inhibitors. Similarly, PROTACs uniquely reduced the expression of genes involved in cell cycle progression, including forkhead box M1 (FOXM1) target genes, in BCa cell lines. Likewise, promoter regions with EZH2 binding in the absence of H3K27me3 were enriched with FOXM1 target genes in both luminal BCa and TNBC cell lines, suggesting a regulatory mechanism independent of hormone receptor status. EZH2 PROTAC treatment reduced FOXM1 protein expression and increased its degradation. In clinical samples, EZH2 mRNA expression tightly correlated with FOXM1 and FOXM1 target genes. Together, this study suggests that EZH2 targeted PROTACs represent a promising avenue of research for the future treatment of BCa, including in the setting of tamoxifen resistance.
2025-05-01 | GSE270163 | GEO
Project description:Breast cancer (BCa) remains the second leading cause of cancer-related mortalities in women, and acquired resistance to hormone therapies, such as tamoxifen, an estrogen receptor inhibitor, is a major hurdle in the treatment of luminal BCa. Another subtype, triple negative BCa (TNBC), is associated with aggressive disease and poor prognosis. The enhancer of zeste homolog 2 (EZH2), the methyltransferase component of the polycomb repressive complex 2 (PRC2), is overexpressed in BCa and has been implicated in tamoxifen resistance. In addition to its PRC2-dependent canonical transcription repressive role through catalyzing histone 3 lysine 27 trimethylation (H3K27me3), evidence suggests that EZH2 can function noncanonically, in a methyltransferase-independent manner, as a transcription activator through interacting with hormone receptors and oncogenic transcription factors. Unlike methyltransferase inhibitors, proteolysis targeting chimeras (PROTAC), which target EZH2 and interacting proteins for degradation, can suppress both activating and repressive functions of EZH2. Previous studies have suggested that PROTACs can be leveraged to inhibit TNBC cell growth. In this study, we expand our scope to test whether EZH2 targeted PROTACs can effectively inhibit luminal BCa cell growth. We find that EZH2-targeted PROTACs, MS177 and MS8815, effectively inhibited the growth luminal BCa cells, including those with acquired tamoxifen resistance, to a much greater degree when compared to methyltransferase inhibitors. Similarly, PROTACs uniquely reduced the expression of genes involved in cell cycle progression, including forkhead box M1 (FOXM1) target genes, in BCa cell lines. Likewise, promoter regions with EZH2 binding in the absence of H3K27me3 were enriched with FOXM1 target genes in both luminal BCa and TNBC cell lines, suggesting a regulatory mechanism independent of hormone receptor status. EZH2 PROTAC treatment reduced FOXM1 protein expression and increased its degradation. In clinical samples, EZH2 mRNA expression tightly correlated with FOXM1 and FOXM1 target genes. Together, this study suggests that EZH2 targeted PROTACs represent a promising avenue of research for the future treatment of BCa, including in the setting of tamoxifen resistance.
2025-05-01 | GSE270769 | GEO
Project description:EZH2-targeted PROTACs target the EZH2/FOXM1 axis and reduce breast cancer cell growth
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Project description:H3K27me3 CUT&Tag analysis of EZH2 mutants in isogenic cell lines
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Project description:We demonstrate that the catalytic subunit of Polycomb Repressive Complex 2, EZH2, is targeted by the MELK-FOXM1 complex, which in turn promotes resistance to radiation in GSCs. Clinically, EZH2 and MELK are co-expressed in GBM and significantly induced in post-irradiation recurrent tumors whose expression inversely correlated with patient prognosis. Through gain-and loss-of-function study, our data show that MELK or FOXM1 contributes on GSC radioresistance by regulation of EZH2. We used microarrays to validate EZH2 target gene expression. GSCs were treated with shNT (control), shMELK, shFOXM1, and EZH2 overexpression. Total RNA was isolated using the Qiagen RNeasy kit (Qiagen).
2015-04-16 | E-GEOD-63963 | biostudies-arrayexpress
Project description:The Enhancer of Zeste 2 Polycomb Repressive Complex 2 Subunit (EZH2) is an essential epigenetic modifier able to methylate lysine 27 on histone H3 (H3K27) to induce chromatin compaction, protein complex recruitment and ultimately transcriptional repression. Hematologic malignancies, including Diffuse Large B cell lymphoma (DLBCL) and Acute myeloid leukemia (AML) have shown a high EZH2-mutation frequency (>20%) associated with poor clinical outcomes. Particularly, two distinct oncogenic mutations, so-called gain-of-function (Y641F and A677G) and loss-of-function (H689A and F667I) are found in the catalytic domain of EZH2. In this study, a comprehensive multi-omics approach was employed to characterize downstream effects of H3K27me3 deposition driven by EZH2 mutations. Human embryonic kidney cells (HEK293T) were transfected to generate three stable EZH2 mutants: EZH2(Y641F), EZH2(A677G), and EZH2(H689A/F667I), which were validated via immunoblotting and DIA-MS-based histone profiling assay. Subsequently, constructs were analyzed under a comprehensive multi-omics approach including: 1) Cleavage Under Targets and Tagmentation (CUT&Tag); 2) chromatin accessibility characterization using the assay for transposase-accessible chromatin with sequencing (ATAC-Seq); 3) transcriptomics (RNA-Seq); 4) label-free whole-cell proteomics, acquired with a Bruker timsTOF Pro HPLC-MS/MS with Ion Mobility, and 5) MS-based untargeted metabolomics, in positive and negative ionization MS/MS mode, acquired with an Agilent 6545 QTOF with a 1290 UHPLC system and HILIC column. Total coverage comprised over 21,000 chromatin regions, 18,000 transcripts, 6,000 proteins and 400 metabolic features. Pair-wise comparison using univariate and supervised multivariate statistical methods revealed significant differences between constructs in each omic level. Furthermore, effector pathway analysis combining omics data revealed distinctive reprogramming effects for each EZH2 mutant.
2023-07-17 | GSE235011 | GEO
Project description:We demonstrate that the catalytic subunit of Polycomb Repressive Complex 2, EZH2, is targeted by the MELK-FOXM1 complex, which in turn promotes resistance to radiation in GSCs. Clinically, EZH2 and MELK are co-expressed in GBM and significantly induced in post-irradiation recurrent tumors whose expression inversely correlated with patient prognosis. Through gain-and loss-of-function study, our data show that MELK or FOXM1 contributes on GSC radioresistance by regulation of EZH2. We used microarrays to validate EZH2 target gene expression.
2015-04-16 | GSE63963 | GEO
Project description:Dissection of melanoma heterogeneity through gene expression profiling has led to the identification of two major phenotypes, conventionally defined as “MITF high / proliferative” and “AXL high / invasive”. Tumors or single melanoma cells characterized by a predominant AXL-related gene program show enhanced expression of sets of genes involved in motility, invasion and regulation of epithelial-mesenchymal transition (EMT), while these genes are downregulated in tumors or cells with a predominant MITF-related gene program. The activation of the AXLhi/MITFlo invasive gene program in melanoma is characterized by aberrant expression of transcription factors (TFs) involved in the embryonic EMT process. Additional master genes involved in promoting melanoma growth and invasive state have been identified within the family of epigenetic regulators. Two of these genes, RNF2 and EZH2, components of the polycomb repressive complexes 1 and 2, act by epigenetically silencing tumor suppressors that in turn regulate the invasive and EMT-like phenotype of melanoma cells. Additional master genes involved in promoting melanoma growth and invasive state have been identified within the family of epigenetic regulators. Two of these genes, RNF2 and EZH2, components of the polycomb repressive complexes 1 and 2, act by epigenetically silencing tumor suppressors that in turn regulate the invasive and EMT-like phenotype of melanoma cells. Here we provide evidence for a new actionable pathway that controls melanoma EMT-like/invasive phenotype. We show that in MITFlo melanomas, the TF NFATc2 controls the EMT-like transcriptional program, the invasive ability of neoplastic cells, as well as in-vitro and in-vivo growth, through a pathway that functionally links c-myc to FOXM1 and EZH2. Targeting of NFATc2, FOXM1 or EZH2 inhibited melanoma migratory and invasive activity. Moreover, pharmacological co-targeting of NFATc2 and EZH2 promoted apoptosis of BRAF-mutant melanomas with intrinsic resistance to BRAF inhibition.
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