journal contribution
posted on 2023-04-03, 20:25 authored by Nami Yamashita, Yoshihiro Morimoto, Atsushi Fushimi, Rehan Ahmad, Atrayee Bhattacharya, Tatsuaki Daimon, Naoki Haratake, Yuka Inoue, Satoshi Ishikawa, Masaaki Yamamoto, Tsuyoshi Hata, Sayuri Akiyoshi, Qiang Hu, Tao Liu, Henry Withers, Song Liu, Geoffrey I. Shapiro, Tomoharu Yoshizumi, Mark D. Long, Donald Kufe <p>S1. Silencing MUC1-C downregulates IRF1 expression in TNBC cells.
S2. Effects of silencing MUC1-C on TNBC cells.
S3. MUC1-C is necessary for PBRM1 expression A and B.
S4. MUC1-C forms a direct complex with IRF1 that activates type I and II ISGs.
S5. Common genes regulated in cells silenced for MUC1, IRF1, and PBRM1.
S6. Silencing MUC1-C, IRF1, and PBRM1 downregulated IDO1 and WARS in TNBC cells.
S7. Silencing of MUC1-C, IRF1, and PBRM1 downregulates RIG-I and MDA5 in TNBC cells.
S8. Silencing MUC1-C, IRF1, and PBRM1 downregulates ISG15 expression in TNBC cells.
S9. Effects of silencing IRF1 and PBRM1 on BT-549 mammosphere formation and GO-203 treatment on the viability of olaparib-resistant MDA-MB-436RR cells.
Table S1. Primers used for qRT-PCR.
Table S2. Primers used for ChIP-qPCR and DNase I chromatin accessibility assays.
Table S3. Common downregulated 196 DEGs in BT-549 cells with silencing of MUC1, IRF1, and PBRM1.
Table S4. Overlapping IFN-pathway genes downregulated in cells with MUC1-C, PBRM1, and IRF1 silencing.</p>
Funding
Cancer Moonshot (Misión contra el Cáncer)
History
ARTICLE ABSTRACT
The polybromo-1 (PBRM1) chromatin-targeting subunit of the SWI/SNF PBAF chromatin remodeling complex drives DNA damage resistance and immune evasion in certain cancer cells through mechanisms that remain unclear. STAT1 and IRF1 are essential effectors of type I and II IFN pathways. Here, we report that MUC1-C is necessary for PBRM1 expression and that it forms a nuclear complex with PBRM1 in triple-negative breast cancer (TNBC) cells. Analysis of global transcriptional (RNA-seq) and chromatin accessibility (ATAC-seq) profiles further demonstrated that MUC1-C and PBRM1 drive STAT1 and IRF1 expression by increasing chromatin accessibility of promoter-like signatures (PLS) on their respective genes. We also found that MUC1-C, PBRM1, and IRF1 increase the expression and chromatin accessibility on PLSs of the (i) type II IFN pathway IDO1 and WARS genes and (ii) type I IFN pathway RIG-I, MDA5, and ISG15 genes that collectively contribute to DNA damage resistance and immune evasion. In support of these results, targeting MUC1-C in wild-type BRCA TNBC cells enhanced carboplatin-induced DNA damage and the loss of self-renewal capacity. In addition, MUC1-C was necessary for DNA damage resistance, self-renewal, and tumorigenicity in olaparib-resistant BRCA1-mutant TNBC cells. Analysis of TNBC tumors corroborated that (i) MUC1 and PBRM1 are associated with decreased responsiveness to chemotherapy and (ii) MUC1-C expression is associated with the depletion of tumor-infiltrating lymphocytes (TIL). These findings demonstrate that MUC1-C activates PBRM1, and thereby chromatin remodeling of IFN-stimulated genes that promote chronic inflammation, DNA damage resistance, and immune evasion.
MUC1-C is necessary for PBRM1-driven chromatin remodeling in chronic activation of IFN pathway genes that promote DNA damage resistance and immunosuppression.
