MUC1-C Dictates JUN and BAF-Mediated Chromatin Remodeling at Enhancer Signatures in Cancer Stem Cells

Abstract

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 (DARs) across their genomes, which are significantly associated with differentially expressed genes (DEGs). 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 stemnessassociated gene enhancers.

MUC1-C integrates type II interferon and chromatin remodeling pathways in immunosuppression of prostate cancer

“… 66 MUC1-C forms complexes with JUN and ARID1A in promoting chromatin accessibility of NOTCH1 and other stemness-associated genes in CRPC cells. 23 In the present work, we found that MUC1-C, JUN and ARID1A form a complex on the IFNGR1 dELS region that induces chromatin accessibility, H3K4 trimethylation and IFNGR1 expression. These findings provided direct evidence for a MUC1-C-induced pathway that integrates induction of ARID1A/BAF with intrinsic activation of the CSC state 23 and IFN-γ pathway in CRPC progression ( Figure 9 ).…”

“…Along these lines, nuclear MUC1-C forms complexes with JUN/AP-1 (Supplemental Fig. S1e) 23 and we detected occupancy of MUC1-C and JUN on the IFNGR1 dELS region ( Figure 2d ). Consistent with JUN-mediated recruitment of the BAF chromatin remodeling complex, 44 we also detected occupancy of ARID1A ( Figure 2d ).…”

“…These results suggest that MUC1 is selectively expressed in CRPC cells with CSC characteristics and chronic inflammatory signaling, linking stemness with immune evasion. In further support of the notion that MUC1-C integrates the CSC state with immune suppression, MUC1-C drives dedifferentiation in triple-negative breast cancer (TNBC) cells 23 , 46 and contributes to suppression of the TNBC immune TME. 69 …”

“…Library preparation and quality control were performed as described. 23 , 31 Peak calling for all libraries was performed using MACS2.…”

Chronic activation of MUC1-C in wound repair promotes progression to cancer stem cells

“…The COMPASS family replaces PcG-driven repressive marks by inducing H3K4 methylation and transcriptional activation [ 53 ] . Emerging evidence indicates that MUC1-C plays a role in driving H3K4 trimethylation of enhancer-like signatures of stemness-associated genes [ 57 ] . Additional studies will therefore be needed to determine whether MUC1-C activates COMPASS and thereby the H3K4me3 mark on these target genes.…”