MUC1-C DICTATES JUN AND BAF-MEDIATED CHROMATIN REMODELING AT PROMOTER AND ENHANCER SIGNATURES IN CANCER STEM CELLS
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE180599 | GEO | 2022/01/19
REPOSITORIES: GEO
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Project description:The oncogenic MUC1-C protein promotes dedifferentiation of castrate-resistant prostate cancer (CRPC) and triple-negative breast cancer (TNBC) cells. Chromatin remodeling is critical for the cancer stem cell (CSC) state; however, there is no definitive evidence that MUC1-C regulates chromatin accessibility and thereby expression of stemness-associated genes. We demonstrate that MUC1-C drives global changes in chromatin architecture in the dedifferentiation of CRPC and TNBC cells. Our results show that MUC1-C induces differentially accessible regions (DAR) across their genomes, which are significantly associated with differentially expressed genes (DEG). Motif and cistrome analysis further demonstrated MUC1-C-induced DARs align with genes regulated by the JUN/AP-1 family of transcription factors. MUC1-C activates the BAF chromatin remodeling complex, which is recruited by JUN in enhancer selection. In studies of the NOTCH1 gene, which is required for CRPC and TNBC cell self-renewal, we demonstrate that MUC1-C is necessary for (i) occupancy of JUN and ARID1A/BAF, (ii) increases in H3K27ac and H3K4me3 signals, and (iii) opening of chromatin accessibility on a proximal enhancer-like signature. Studies of the EGR1 and LY6E stemness-associated genes further demonstrate that MUC1-C-induced JUN/ARID1A complexes regulate chromatin accessibility on proximal and distal enhancer-like signatures. These findings uncover a role for MUC1-C in chromatin remodeling that is mediated at least in part by JUN/AP-1 and ARID1A/BAF in association with driving the CSC state.ImplicationsThese findings show that MUC1-C, which is necessary for the CRPC and TNBC CSC state, activates a novel pathway involving JUN/AP-1 and ARID1A/BAF that regulates chromatin accessibility of stemness-associated gene enhancers.
| S-EPMC8983489 | biostudies-literature
Project description:MUC1-C DICTATES JUN AND BAF-MEDIATED CHROMATIN REMODELING AT PROMOTER AND ENHANCER SIGNATURES IN CANCER STEM CELLS
| PRJNA748762 | ENA
Project description:MUC1-C drives neuroendocrine lineage plasticity in pancreatic adenocarcinomas
2021-08-13 | GSE181961 | GEO
Project description:STAT1 and IRF1 are essential effectors of the type I and II interferon (IFN) pathways. Here, we report that the oncogenic MUC1-C protein is necessary for inducing chromatin accessibility and activation of the STAT1 and IRF1 genes in triple-negative breast cancer (TNBC) cells. Our results demonstrate that MUC1-C activates the PBRM1 subunit of the SWI/SNF PBAF chromatin remodeling complex and forms a nuclear complex with PBRM1. We show that MUC1-C associates with PBRM1 and STAT1 on the IRF1 gene at (i) a proximal enhancer-like signature (PLS), and (ii) distal enhancer-like signatures (dELSs). We also show MUC1-C and PBRM1 are necessary for opening chromatin at these signatures and for the induction of IRF1 expression. In extending these results, we found that MUC1-C binds directly to IRF1 and forms nuclear complexes with PBRM1 and IRF1, which are necessary for inducing chromatin accessibility at PLS of the (i) STAT1 gene, (ii) type II IFN pathway IDO1 and WARS genes, and (iii) type I IFN pathway RIG-I, MDA5 and ISG15 genes. Consistent with involvement of chronic inflammation in promoting the cancer stem cell (CSC) state, we show that MUC1-C, PBRM1 and IRF1 are required for self-renewal of TNBC CSCs. Of translational relevance, we report that targeting MUC1-C, PBRM1 and IRF1 circumvents intrinsic DNA damage resistance of TNBC CSCs and that MUC1-C is necessary for acquired resistance to the PARP inhibitor olaparib. These findings demonstrate that MUC1-C activates PBRM1/IRF1 and thereby chromatin remodeling of IFN pathway genes that promote chronic inflammation, the CSC state and DNA damage resistance.
2023-06-14 | GSE212587 | GEO
Project description:Mucin 1 (MUC1) is a transmembrane mucin expressed at the apical surface of epithelial cells at different mucosal surfaces including breast and intestine. The MUC1 extracellular domain contains a variable number of tandem repeats (VNTR) of 20 amino acids, which are heavily O-linked glycosylated. Monoclonal antibodies against the MUC1 VNTR can be powerful tools because of their multiplicity of binding and possible applications in the diagnosis and treatment of MUC1-expressing cancers. One such antibody is the hybridoma mouse monoclonal 139H2 which is also widely used as a research tool to study non-cancer MUC1. Here we report direct mass spectrometry-based sequencing of hybridoma-derived 139H2 IgG, which enabled reverse engineering of a recombinant 139H2.
2024-03-18 | PXD043489 | Pride
Project description:The cancer stem cell (CSC) state is intimately associated with suppression of the immune tumor microenvironment (TME). The oncogenic MUC1-C protein drives dedifferentiation of castrate resistant prostate cancer (CRPC) CSCs in association with induction of the BAF, NuRD and PBAF chromatin remodeling complexes. The present work demonstrates that MUC1-C is necessary for expression of IFNGR1 and activation of the type II interferon-gamma (IFN- pathway in CRPC cells. We show that the MUC1-CARID1A/BAF pathway induces IFNGR1 transcription and that MUC1-CNuRD signaling suppresses FBXW7 in stabilizing the IFNGR1 protein. MUC1-C and NuRD were also necessary for expression of the downstream STAT1 and IRF1 transcription factors. Additionally and in contrast, our results demonstrate that MUC1-C and the PBRM1/PBAF pathway are necessary for IRF1-induced expression of (i) IDO1, WARS and PTGES, which metabolically suppress the immune TME, and (ii) the ISG15 and SERPINB9 inhibitors of T cell function. Of translational relevance, we show that MUC1 associates with expression of IFNGR1, STAT1 and IRF1, as well as the downstream IDO1, WARS, PTGES, ISG15 and SERPINB9 immunosuppressive effectors in CRPC tumors. Consistent with these results, MUC1 associates with immune cell-depleted “cold” CRPC TMEs. These findings demonstrate that MUC1-C integrates chronic activation of the type II IFN-G pathway with induction of chromatin remodeling complexes in linking CSC dedifferentiation and immune evasion.
2022-01-19 | GSE184896 | GEO
Project description:Goal of study: To determine differentially expressed genes with potential roles in tolerance and immunity in MUC1-immunized WT and MUC1.Tg mice WT (C57Bl/6) and MUC1.Tg mice were immunized (i.v.) with dendritic cells loaded with sythetic, human MUC1 peptide. At 24h and 72h splenic RNA from vaccination groups (n=3) was pooled and microarray performed.
2013-01-16 | E-GEOD-43503 | biostudies-arrayexpress
Project description:To determine if overexpression of MUC1 alters the microRNA profile of pancreatic cancer cells S2.013. Comparison of miRNAs differentially regulated in pancreatic cancer cell line S2.013 with and without MUC1 overexpression. MiRCURY LNA microarray was used to determine differential microRNA expression in one replicate of S2.013.Neo (control) cells compared to S2.013.MUC1 (experimental) cells. Confirmation with qRT-PCR was performed on a subset of microRNAs identified as differentially regulated between the two groups.
2013-08-10 | E-GEOD-48185 | biostudies-arrayexpress
Project description:STAT1 and IRF1 are essential effectors of the type I and II interferon (IFN) pathways. Here, we report that the oncogenic MUC1-C protein is necessary for inducing chromatin accessibility and activation of the STAT1 and IRF1 genes in triple-negative breast cancer (TNBC) cells. Our results demonstrate that MUC1-C activates the PBRM1 subunit of the SWI/SNF PBAF chromatin remodeling complex and forms a nuclear complex with PBRM1. We show that MUC1-C associates with PBRM1 and STAT1 on the IRF1 gene at (i) a proximal enhancer-like signature (pELS), and (ii) distal enhancer-like signatures (dELSs). We also show MUC1-C and PBRM1 are necessary for opening chromatin at these signatures and for the induction of IRF1 expression. In extending these results, we found that MUC1-C binds directly to IRF1 and forms nuclear complexes with PBRM1 and IRF1, which are necessary for inducing chromatin accessibility at pELSs of the (i) STAT1 gene, (ii) type II IFN pathway IDO1 and WARS genes, and (iii) type I IFN pathway RIG-I, MDA5 and ISG15 genes. Consistent with involvement of chronic inflammation in promoting the cancer stem cell (CSC) state, we show that MUC1-C, PBRM1 and IRF1 are required for self-renewal of TNBC CSCs. Of translational relevance, we report that targeting MUC1-C, PBRM1 and IRF1 circumvents intrinsic DNA damage resistance of TNBC CSCs and that MUC1-C is necessary for acquired resistance to the PARP inhibitor olaparib. These findings demonstrate that MUC1-C activates PBRM1 and thereby chromatin remodeling of IFN pathway genes that promote chronic inflammation, the CSC state and DNA damage resistance.
2022-06-21 | GSE206212 | GEO
Project description:We identified a novel E2 ubiquitin conjugating activity within the C-terminus domain of MUC1. To determine if E2 ubiquitin conjugating activity of MUC1 is responsible for regulating expression of oncogenic genes we isolated RNA from vector control cells, MUC1 wildtype overexpression cells, and cells that express a serine mutant lacking E2 activity. RNA was isolated from each of the 3 cell lines, S2013.Neo, S2013.MUC1-WT, and S2013.MUC1-Ser. Gene expression was analyzed by spotted microarray and the differences in gene expression were calculated between the cell lines
2016-08-01 | E-GEOD-60339 | biostudies-arrayexpress