MUC1-C Activates the NuRD Complex to Drive Dedifferentiation of Triple-Negative Breast Cancer Cells

Abstract

The NuRD chromatin remodeling and deacetylation complex, which includes MTA1, MBD3, CHD4, and HDAC1 among other components, is of importance for development and cancer progression. The oncogenic mucin 1 (MUC1) Cterminal subunit (MUC1-C) protein activates EZH2 and BMI1 in the epigenetic reprogramming of triple-negative breast cancer (TNBC). However, there is no known link between MUC1-C and chromatin remodeling complexes. Here, we showed that MUC1-C binds directly to the MYC HLH-LZ domain and identified a previously unrecognized MUC1-C!MYC pathway that regulates the NuRD complex. MUC1-C/MYC complexes selectively activated the MTA1 and MBD3 genes and posttranscriptionally induced CHD4 expression in basal-but not luminal-type BC cells. In turn, MUC1-C formed complexes with these NuRD components on the ESR1 promoter. Downregulating MUC1-C decreased MTA1/MBD3/ CHD4/HDAC1 occupancy and increased H3K27 acetylation on the ESR1 promoter, with induction of ESR1 expression and downstream estrogen response pathways. Targeting MUC1-C and these NuRD components also induced expression of FOXA1, GATA3, and other markers associated with the luminal phenotype. These findings support a model in which MUC1-C activates the NuRD complex to drive dedifferentiation and reprogramming of TNBC cells.Significance: MUC1-C directly interacts with MYC to activate the NuRD complex, mediating regulation of the estrogen receptor in triple-negative breast cancer cells.

MUC1-C regulates lineage plasticity driving progression to neuroendocrine prostate cancer

“…We also found that silencing MUC1-C decreases MYC occupancy ( Fig. 3d), consistent with involvement of MUC1-C in enhancing MYC transactivation complexes 23 . Functional studies performed with a BRN2 promoter-luciferase reporter (pBRN2-Luc) demonstrated suppression of activity by (i) mutating the distal, but not proximal, MYC binding site (Fig.…”

“…MUC1-C activates MYC expression in certain cancer cells [28][29][30] . In addition, the MUC1-C cytoplasmic domain binds directly to the MYC HLH-LZ region and, as a result, MUC1-C forms a complex with MYC on the promoters of MYC target genes 23 . Along those lines, we identified putative MYC binding sites in the BRN2 promoter ( Fig.…”

“…In the present studies, targeting NF-κB p65 genetically or with the BAY-11-7085 inhibitor had no effect on BRN2 expression. In addition to NF-κB, MUC1-C activates the MYC pathway, binds directly to the MYC HLH/LZ domain and promotes occupancy of MYC on its target genes 23,28,29 . In this respect, we identified an E-box as a MYC binding site that functions in activating the BRN2 promoter.…”

“…In cancer cells, MUC1-C associates with receptor tyrosine kinases, such as EGFR among others, at the cell membrane and contributes to activation of their downstream pathways 14,16 . MUC1-C is imported into the nucleus, where it interacts directly with TFs, including MYC and p53, and thereby regulates their transactivation functions 16,22,23 . MUC1-C is also involved in epigenetic reprogramming by activating (i) DNA methyltransferases (DNMTs), (ii) components of PRC1/2, including EZH2, and (iii) the NuRD chromatin remodeling complex, further supporting a role for MUC1-C in gene regulation, including the repression of tumor suppressor genes (TSGs) 15,16,23,24 .…”

Role of Chromodomain-Helicase-DNA-Binding Protein 4 (CHD4) in Breast Cancer

“…In vitro experiments have recently suggested that CHD4 depletion may be a therapeutic target in different types of BC, as it could lead to reduced tumor proliferation, migration, invasiveness, and growth ( 27 , 28 , 61 – 64 ) ( Figure 2 ). Thus, CHD4 status could determine the response of BC patients to current treatments, and pharmacological inhibition or targeting of CHD4 expression could improve the clinical outcome in breast cancer patients according to breast cancer type.…”