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| Status |
Public on Jun 21, 2022 |
| Title |
Muc1-C Induces Pbrm1-Mediated Chromatin Remodeling in Driving Chronic Inflammation and DNA Damage Resistance in Triple-Negative Breast Cancer |
| 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 (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.
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| Overall design |
RNA-seq in breast cancer cell lines
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| Contributor(s) |
Yamashita N |
| Citation(s) |
36445328 |
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| Submission date |
Jun 15, 2022 |
| Last update date |
Jun 14, 2023 |
| Contact name |
Nami Yamashita |
| E-mail(s) |
namanaminy0117@gmail.com
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| Organization name |
Dana-Farber Cancer Institute
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| Department |
Medical Oncology
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| Lab |
Kufe Lab
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| Street address |
450 Brookline Avenue
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| City |
Boston |
| State/province |
MA |
| ZIP/Postal code |
02215 |
| Country |
USA |
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| Platforms (1) |
| GPL24676 |
Illumina NovaSeq 6000 (Homo sapiens) |
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| Samples (18)
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| GSM6246240 |
MDAMB436/tet-MUC1shRNA, DOX+, rep1 |
| GSM6246241 |
MDAMB436/tet-MUC1shRNA, DOX+, rep2 |
| GSM6246242 |
MDAMB436/tet-MUC1shRNA, DOX+, rep3 |
| GSM6246243 |
BT549/control for shPBRM1, rep1 |
| GSM6246244 |
BT549/control for shPBRM1, rep2 |
| GSM6246245 |
BT549/control for shPBRM1, rep3 |
| GSM6246246 |
BT549/shPBRM1, rep1 |
| GSM6246247 |
BT549/shPBRM1, rep2 |
| GSM6246248 |
BT549/shPBRM1, rep3 |
| GSM6246249 |
BT549/control for shIRF1, rep1 |
| GSM6246250 |
BT549/control for shIRF1, rep2 |
| GSM6246251 |
BT549/control for shIRF1, rep3 |
| GSM6246252 |
BT549/shIRF1, rep1 |
| GSM6246253 |
BT549/shIRF1, rep2 |
| GSM6246254 |
BT549/shIRF1, rep3 |
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| Relations |
| BioProject |
PRJNA849622 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE206212_BT549_shIRF1_Gene_TPM.csv.gz |
1.1 Mb |
(ftp)(http) |
CSV |
| GSE206212_BT549_shIRF1vControl.deseq.csv.gz |
1.1 Mb |
(ftp)(http) |
CSV |
| GSE206212_BT549_shPBRM1_Gene_TPM.csv.gz |
710.1 Kb |
(ftp)(http) |
CSV |
| GSE206212_BT549_shPBRM1_v_Control.deseq.csv.gz |
977.9 Kb |
(ftp)(http) |
CSV |
| GSE206212_MDAMB436-t8_Gene_TPM.csv.gz |
976.4 Kb |
(ftp)(http) |
CSV |
| GSE206212_MDAMB436_Dox_v_noDox.deseq_star.csv.gz |
952.9 Kb |
(ftp)(http) |
CSV |
SRA Run Selector |
| Raw data are available in SRA |
| Processed data are available on Series record |
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