MUC1-C intersects chronic inflammation with epigenetic reprogramming by regulating the set1a compass complex in cancer progression

Abstract

Chronic inflammation promotes epigenetic reprogramming in cancer progression by pathways that remain unclear. The oncogenic MUC1-C protein is activated by the inflammatory NF-κB pathway in cancer cells. There is no known involvement of MUC1-C in regulation of the COMPASS family of H3K4 methyltransferases. We find that MUC1-C regulates (i) bulk H3K4 methylation levels, and (ii) the COMPASS SET1A/SETD1A and WDR5 genes by an NF-κB-mediated mechanism. The importance of MUC1-C in regulating the SET1A COMPASS complex is supported by the demonstration that MUC1-C and WDR5 drive expression of FOS, ATF3 and other AP-1 family members. In a feedforward loop, MUC1-C, WDR5 and AP-1 contribute to activation of genes encoding TRAF1, RELB and other effectors in the chronic NF-κB inflammatory response. We also show that MUC1-C, NF-κB, WDR5 and AP-1 are necessary for expression of the (i) KLF4 master regulator of the pluripotency network and (ii) NOTCH1 effector of stemness. In this way, MUC1-C/NF-κB complexes recruit SET1A/WDR5 and AP-1 to enhancer-like signatures in the KLF4 and NOTCH1 genes with increases in H3K4me3 levels, chromatin accessibility and transcription. These findings indicate that MUC1-C regulates the SET1A COMPASS complex and the induction of genes that integrate NF-κB-mediated chronic inflammation with cancer progression.

Identification of Muc1-C as a Target for Suppressing Progression of Head and Neck Squamous Cell Carcinomas

“…Nascent RNA labeling with ethylene uridine (EU) was performed using the Click-iT Nascent RNA Capture kit (Invitrogen) as described previously ( 29 ). Cells were pulsed with 0.5 mmol/L EU for 24 hours and nascent transcripts were captured from isolated total RNA on streptavidin magnetic beads.…”

The occurrence and development of induced pluripotent stem cells

“…It has been confirmed that there is an important connection between epigenetic changes and reprogramming, and epigenetic-modifying factors play an indispensable role in reprogramming ( Mao et al, 2017 ). However, the accumulation of epigenetic changes (such as acetylation or methylation) increases the risk of cancer, especially those associated with chronic inflammation ( Bhattacharya et al, 2023 ; Chen et al, 2023 ; de Lima et al, 2023 ; Song et al, 2023 ). Some enzymes that regulate posttranslational modifications of histones can also promote cell fate toward pluripotency or differentiation by overexpressing or downregulating genes related to pluripotency, thereby affecting epigenetic modifications of transcription ( Figure 2 ).…”

MUC1-C regulates NEAT1 lncRNA expression and paraspeckle formation in cancer progression

“…However, prolonged activation of MUC1-C in response to chronic inflammation promotes progression to cancer [14,15]. MUC1-C induces (i) loss of polarity [16], (ii) the epithelial-mesenchymal transition (EMT) [17,18], and (iii) epigenetic reprogramming by the Polycomb Repressive Complexes (PRC1/2) and COMPASS family of H3K4 methyltransferases [19][20][21][22][23]. MUC1-C also regulates the nucleosome remodeling and deacetylation (NuRD) complex [24] and the SWI/SNF BAF [25] and PBAF [26] chromatin remodeling complexes.…”

“…MUC1-C also regulates the nucleosome remodeling and deacetylation (NuRD) complex [24] and the SWI/SNF BAF [25] and PBAF [26] chromatin remodeling complexes. In this way, MUC1-C drives global changes in chromatin architecture with increases in accessibility of enhancer-like sequences in stemness-associated genes that contribute to the cancer stem cell (CSC) state [23,27]. CSCs are dependent on MUC1-C for self-renewal capacity and tumorigenicity [28][29][30][31][32][33].…”