Abstract A032: MUC1-C regulates chromatin remodeling and drives the CSC state in human cancers

Abstract

Abstract The oncogenic MUC1-C protein evolved in mammals to protect epithelial barrier tissues from the external environment. Chronic activation of MUC1-C promotes lineage plasticity, epigenetic reprogramming, and carcinogenesis. MUC1-C also induces the Yamanaka Pluripotency factors. Chromatin remodeling is critical for the cancer stem cell (CSC) state. Our studies have demonstrated that MUC1-C regulates chromatin remodeling by (i) activating the EZH2/PRC2 complex leading to H3K27 trimethylation, and (ii) the BMI1/PRC1 complex with H2A ubiquitylation. In addition, MUC1-C regulates global changes in chromatin accessibility that are mediated at least in part by JUN/AP-1 and ARID1A/BAF in association with driving the CSC state. We also found that silencing MUC1-C suppresses bulk H3K4 trimethylation and H3K27 acetylation levels in diverse human cancer cells. The COMPASS family of H3K4 methyl transferases (HMT) methylate histone H3K4 and the histone acetyl transferase (HAT) p300/CBP family catalyzes H3K27 acetylation. Involvement of MUC1-C in the regulation of COMPASS has not been previously reported. This study demonstrates that MUC1-C induces COMPASS SET1A and WDR5 gene expression by NF-kB p65-mediated transactivation. WDR5 is required for SET1A complex HMT activity. We found that MUC1-C and WDR5 are necessary for expression of FOS, ATF3 and other AP-1 family members. In a positive feedback loop, MUC1-C, WDR5 and AP-1 were shown to be responsible for induction of genes encoding effectors, including TRAF1 and RELB, in the chronic NF-kB inflammatory response. We also found that MUC1-C, NF-kB, WDR5 and AP-1 are necessary for induction of the (i) KLF4 master regulator of the pluripotency network, and (ii) NOTCH1 effector of stemness. Mechanistically, MUC1-C/NF-kB complexes recruit SET1A/WDR5 and AP-1 to enhancer-like signatures in these target genes, increase the deposition of H3K4me3 with the opening of chromatin, and activate their transcription. These findings demonstrate that MUC1-C activates the COMPASS SET1A/WDR5 complex in integrating the induction of genes that promote chronic inflammation, pluripotency, and the CSC state. Citation Format: trayee Bhattacharya, Atsushi Fushimi, Nami Yamashita, Tao Liu, Song Liu, Donald W. Kufe. MUC1-C regulates chromatin remodeling and drives the CSC state in human cancers. [abstract]. In: Proceedings of the AACR Special Conference: Cancer Epigenomics; 2022 Oct 6-8; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2022;82(23 Suppl_2):Abstract nr A032.