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| Status |
Public on Jun 14, 2023 |
| Title |
MUC1-C INDUCES PBRM1-MEDIATED CHROMATIN REMODELING IN DRIVING CHRONIC INFLAMMATION AND DNA DAMAGE RESISTANCE IN TRIPLE-NEGATIVE BREAST CANCER [tet-MUC1 shRNA] |
| Organism |
Homo sapiens |
| Experiment type |
Expression profiling by high throughput sequencing
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| Summary |
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.
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| Overall design |
MDA-MB-436 cells stably expressing a tet-MUC1 shRNA vector were treated with 0.1% DMSO as the vehicle control or 500 ng/ml doxycycline. Total RNA from cells cultured in triplicates was isolated and used for library preparation.
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| Contributor(s) |
Yamashita N, Kufe D, Long M, Hu Q |
| Citation(s) |
36445328 |
| |
| Submission date |
Sep 02, 2022 |
| Last update date |
Jun 14, 2023 |
| Contact name |
Qiang Hu |
| E-mail(s) |
Qiang.Hu@RoswellPark.org
|
| Organization name |
Roswell Park Cancer Institute
|
| Street address |
Elm & Carlton Streets
|
| City |
Buffalo |
| State/province |
NY |
| ZIP/Postal code |
14263 |
| Country |
USA |
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| Platforms (1) |
| GPL24676 |
Illumina NovaSeq 6000 (Homo sapiens) |
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| Samples (6)
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| This SubSeries is part of SuperSeries: |
| GSE212170 |
MUC1-C INDUCES PBRM1-MEDIATED CHROMATIN REMODELING IN DRIVING CHRONIC INFLAMMATION AND DNA DAMAGE RESISTANCE IN TRIPLE-NEGATIVE BREAST CANCER |
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| Relations |
| BioProject |
PRJNA876139 |
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