MLL3 Loss Drives Metastasis by Promoting a Hybrid Epithelial-Mesenchymal Transition State [RNA-seq MDA231 KO vs WT]
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE206655 | GEO | 2022/10/07
REPOSITORIES: GEO
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Project description:Loss of MLL3 facilitates mesenchymal cells to acquire a mesenchymal/epithelial hybrid state during metastatic colonization. The MET occurring in distant metastases is likely driven by stromal signals in the metastatic niche. One signaling pathway that promotes the MET is the activation of protein kinase A (PKA). The MET hybrid cells can be identified as CD44+CD104+/high. Forskolin treatment generated significantly more CD44+CD104high hybrid cells in MLL3-mutant cells than the WT MDA-MB-231 cells. While both WT and MLL3-mutant CD44+CD104high hybrid EMT cells showed significantly increased lung metastatic ability than the counterpart CD44+CD104low mesenchymal cells, the MLL3-mutant hybrid cells showed a much greater metastasis-initiating ability than the WT hybrid cells. Here we reported the gene expression profiles of CD44+CD104high E/M hybird and CD44+CD104-/low mesenchymal cell populations sorted from Foskolin-treated, MLL3-null MDA-MB-231 cells.
2022-10-07 | GSE171444 | GEO
Project description:Phenotypic plasticity associated with the hybrid epithelial-mesenchymal transition (EMT) state is crucial to metastatic seeding and outgrowth. We showed that deletion of the epigenetic regulator MLL3, a tumor suppressor frequently altered in human cancer, promoted the acquisition of the hybrid EMT state in both epithelial and mesenchymal breast cancer cells by facilitating EMT and MET, distinct from other known EMT regulators mediating unidirectional changes. MLL3 deletion greatly increased metastasis by enhancing metastatic outgrowth during colonization. Mechanistically, MLL3 loss led to IFNγ signaling upregulation, which contributes to the induction of hybrid EMT cells and the enhanced metastatic capacity.
2022-10-07 | GSE206658 | GEO
Project description:Phenotypic plasticity associated with the hybrid epithelial-mesenchymal transition (EMT) state is crucial to metastatic seeding and outgrowth. However, the mechanisms controlling the induction of hybrid EMT remain poorly defined. We showed that deletion of the epigenetic regulator MLL3, a tumor suppressor frequently altered in human cancer, promoted the acquisition of the hybrid EMT state in both epithelial and mesenchymal breast cancer cells by facilitating EMT and MET, distinct from other known EMT regulators mediating unidirectional changes. Consequently, MLL3 deletion greatly increased metastasis by enhancing metastatic outgrowth during colonization. Mechanistically, MLL3 loss led to IFNγ signaling upregulation, which contributes to the induction of hybrid EMT cells and the enhanced metastatic capacity.
2022-10-07 | GSE206656 | GEO
Project description:Loss of MLL3 facilitates mesenchymal cells to acquire a mesenchymal/epithelial hybrid state during metastatic colonization. The MET occurring in distant metastases is likely driven by stromal signals in the metastatic niche. One signaling pathway that promotes the MET is the activation of protein kinase A (PKA). The MET hybrid cells can be identified as CD44+CD104+/high. Forskolin treatment generated significantly more CD44+CD104high hybrid cells in MLL3-mutant cells than the WT MDA-MB-231 cells. While both WT and MLL3-mutant CD44+CD104high hybrid EMT cells showed significantly increased lung metastatic ability than the counterpart CD44+CD104low mesenchymal cells, the MLL3-mutant hybrid cells showed a much greater metastasis-initiating ability than the WT hybrid cells. Here we reported the gene expression profiles of CD44+CD104high E/M hybird and CD44+CD104-/low mesenchymal cell populations sorted from Foskolin-treated, WT MDA-MB-231 cells.
2022-10-07 | GSE206653 | GEO
Project description:Phenotypic plasticity associated with the hybrid epithelial-mesenchymal transition (EMT) state is crucial to metastatic seeding and outgrowth. However, the mechanisms controlling the induction of hybrid EMT remain poorly defined. We showed that deletion of the epigenetic regulator MLL3, a tumor suppressor frequently altered in human cancer, promoted the acquisition of the hybrid EMT state in both epithelial and mesenchymal breast cancer cells by facilitating EMT and MET, distinct from other known EMT regulators mediating unidirectional changes. Consequently, MLL3 deletion greatly increased metastasis by enhancing metastatic outgrowth during colonization. Mechanistically, MLL3 loss led to IFNγ signaling upregulation, which contributes to the induction of hybrid EMT cells and the enhanced metastatic capacity.
2022-10-07 | GSE206657 | GEO
Project description:a.Background Cancer resequencing studies have revealed epigenetic enzymes as common targets for recurrent mutations. The monomethyltransferase MLL3 is among the most recurrently mutated enzymes in ER+ breast cancer. The H3K4me1 marks created by MLL3 can define enhancers. In ER+ breast cancer, ERα genome binding sites are primarily distal enhancers. Thus, we hypothesize that mutation of MLL3 will alter the genomic binding and transcriptional regulatory activity of ERα. b.Methods We investigated the genomic consequences of knocking down MLL3 in an MLL3/PIK3CA WT ER+ breast cancer cell line. c. Results Loss of MLL3 led to large loss of H3K4me1 across the genome, and a shift in ERα binding sites, which was accompanied by a re-organization of the breast cancer transcriptome. Enrichment analyses of ERα binding sites in MLL3 KD identified endocrine therapy resistance terms, and we show that MLL3 KD cells are resistant to tamoxifen and fulvestrant. Many differentially expressed genes are controlled by new locations of H3K4me1 deposition and ERα binding, suggesting that loss of functional MLL3 leads to new transcriptional regulation of essential genes. Motif analysis of RNA-seq and ChIP-seq data highlighted SP1 as a critical transcription factor in the MLL3 KD cells. Loss of ERα binding is accompanied by a massive increase in SP1 binding at differentially expressed genes. d.Conclusions Our data show that loss of functional MLL3 leads to endocrine therapy resistance. This highlights the importance of genotyping patient tumor samples for MLL3 mutation upon initial resection, prior to deciding upon treatment plans.
2020-12-16 | GSE163264 | GEO
Project description:An imbalance in the activities of the Polycomb and Trithorax complexes underlies numerous human pathologies, including cancer. The BAP1 deubiquitinase (DUB) complex negatively regulates Polycomb activity and also recruits the Trithorax histone H3K4 methyltransferase, MLL3/COMPASS, to the enhancers of tumor suppressor genes. We and others have demonstrated that the BAP1-MLL3 pathway is mutated in several differ cancers. Yet, how BAP1 recruits MLL3 to these loci remains a fundamentally important unanswered question. Here we demonstrate that ASXL2 directly mediates the interaction between the BAP1 complex and MLL3/COMPASS. ASXL2 loss abolishes the MLL3-BAP1 interaction, leading to decreased MLL3 occupancy at enhancers and reduced expression of BAP1-MLL3 target genes. The interaction between ASXL2 and MLL3 is negatively regulated by protein arginine methyltransferase 4 (PRMT4, also known as CARM1), which methylates ASXL2 on R639/R641. Methylation of ASXL2 by CARM1 blocks binding to MLL3 binding and impairs the expression of MLL3 dependent genes. This finding uncovers a novel transcription repression function for CARM1 and provides a unique insight into the BAP1/ASXL2/MLL3 axis, which is controlled by arginine methylation and could serve as a target for potential cancer therapeutics.
2022-08-12 | GSE182625 | GEO
Project description:Epigenetic alterations due to abnormalities in the enzymatic machineries modifying chromatin, are frequently reported in developmental diseases and in a variety of human cancers. However, the cellular dependency and functional outcome of epigenetic alterations during these processes have not been fully elucidated. In this study, we depleted two of the most frequently mutated epigenetic factors, the MLL3 and MLL4 components of the COMPASS family, in mouse embryonic stem cells (mESCs) to investigate the cellular vulnerabilities when enhancer functions are compromised as the result of MLL3-4/COMPASS loss. CRISPR dropout screens revealed synthetic lethality of purine and pyrimidine nucleotide synthesis pathway suppression in cells with MLL3/4 loss. We observed a metabolic usage shift towards purine synthesis in Mll3/4 knockout mESCs. Subsequently, Mll3/4 KO cells exhibited enhanced sensitivity to purine synthesis inhibitor lometrexol, which induced unique gene expression signature changes in Mll3/4 KO cells. A tandem mass tag (TMT) proteomics profiling further identified upregulation of purine metabolism factors in Mll3/4KO cells. We also identified the top MLL3/4 target genes coinciding with suppression of the purine metabolism pathway. Finally, in vivo cancer studies show that tumors mutated for MLL3 and/or MLL4 are very sensitive to purine synthesis inhibitor lometrexol in culture and in animal models of cancer. Taken together, we depict a metabolic dependency map for cells deficient for epigenetic factors and provide insights into cancer treatments related to epigenetic alterations corresponding with MLL3/4 COMPASS malfunction.
2023-06-01 | GSE200120 | GEO
Project description:FOXA1 is a pioneer factor that is important in hormone dependent cancer cells to stabilise nuclear receptors, such as estrogen receptor (ER) to chromatin. FOXA1 binds to enhancers regions that are enriched in H3K4mono- and dimethylation (H3K4me1, H3K4me2) histone marks and evidence suggests that these marks are requisite events for FOXA1 to associate with enhancers to initate subsequent gene expression events. However, exogenous expression of FOXA1 has been shown to induce H3K4me1 and H3K4me2 signal at enhancer elements and the order of events and the functional importance of these events is not clear. We performed a FOXA1 Rapid Immunoprecipitation Mass Spectrometry of Endogenous Proteins (RIME) screen in ERα-positive MCF-7 breast cancer cells in order to identify FOXA1 interacting partners and we found histone-lysine N-methyltransferase (MLL3) as the top FOXA1 interacting protein. MLL3 is typically thought to induce H3K4me3 at promoter regions, but recent findings suggest it may contribute to H3K4me1 deposition, in line with our observation that MLL3 associates with an enhancer specific protein. We performed MLL3 ChIP-seq in breast cancer cells and unexpectedly found that MLL3 binds mostly at non-promoter regions enhancers, in contrast to the prevailing hypothesis. MLL3 was shown to occupy regions marked by FOXA1 occupancy and as expected, H3K4me1 and H3K4me2. MLL3 binding was dependent on FOXA1, indicating that FOXA1 recruits MLL3 to chromatin. Motif analysis and subsequent genomic mapping revealed a role for Grainy head like protein-2 (GRHL2) which was shown to co-occupy regions of the chromatin with MLL3. Regions occupied by all three factors, namely FOXA1, MLL3 and GRHL2, were most enriched in H3K4me1. MLL3 silencing decreased H3K4me1 at enhancer elements, but had no appreciable impact on H3K4me3 at enhancer elements. We identify a complex relationship between FOXA1, MLL3 and H3K4me1 at enhancers in breast cancer and propose a mechanism whereby the pioneer factor FOXA1 can interact with a chromatin modifier MLL3, recruiting it to chromatin to facilitate the deposition of H3K4me1 histone marks, subsequently demarcating active enhancer elements.
2016-12-12 | PXD005253 | Pride
Project description:Epithelial to Mesenchymal Transition (EMT) has been associated with cancer cell heterogeneity, plasticity and metastasis. It has been the subject of several modeling effort. This logical model of the EMT cellular network aims to assess microenvironmental signals controlling cancer-associated phenotypes amid the EMT continuum. Its outcomes relate to the qualitative degrees of cell adhesions by adherent junctions and focal adhesions, two features affected during EMT. Model attractors recover epithelial, mesenchymal and hybrid phenotypes, and simulations show that hybrid phenotypes may arise through independent molecular paths, involving stringent extrinsic signals.
Of particular interest, model predictions and their experimental validations indicated that: 1) ECM stiffening is a prerequisite for cells overactivating FAK-SRC to upregulate SNAIL1 and acquire a mesenchymal phenotype, and 2) FAK-SRC inhibition of cell-cell contacts through the Receptor Protein Tyrosine Phosphates kappa leads to the acquisition of a full mesenchymal rather than a hybrid phenotype.
2020-06-30 | MODEL2004040001 | BioModels