The epigenetic regulator Mll1 is required for Wnt-driven intestinal tumorigenesis and cancer stemness

Abstract

Wnt/β-catenin signaling is crucial for intestinal carcinogenesis and the maintenance of intestinal cancer stem cells. Here we identify the histone methyltransferase Mll1 as a regulator of Wnt-driven intestinal cancer. Mll1 is highly expressed in Lgr5+ stem cells and human colon carcinomas with increased nuclear β-catenin. High levels of MLL1 are associated with poor survival of colon cancer patients. The genetic ablation of Mll1 in mice prevents Wnt/β-catenin-driven adenoma formation from Lgr5+ intestinal stem cells. Ablation of Mll1 decreases the self-renewal of human colon cancer spheres and halts tumor growth of xenografts. Mll1 controls the expression of stem cell genes including the Wnt/β-catenin target gene Lgr5. Upon the loss of Mll1, histone methylation at the stem cell promoters switches from activating H3K4 tri-methylation to repressive H3K27 tri-methylation, indicating that Mll1 sustains stem cell gene expression by antagonizing gene silencing through polycomb repressive complex 2 (PRC2)-mediated H3K27 tri-methylation. Transcriptome profiling of Wnt-mutated intestinal tumor-initiating cells reveals that Mll1 regulates Gata4/6 transcription factors, known to sustain cancer stemness and to control goblet cell differentiation. Our results demonstrate that Mll1 is an essential epigenetic regulator of Wnt/β-catenin-induced intestinal tumorigenesis and cancer stemness.

Genome-scale CRISPR-Cas9 screen of Wnt/β-catenin signaling identifies therapeutic targets for colorectal cancer

“…Last, the ability of β-catenin and KMT2A to impinge on cancer stemness is of particular interest and highlights a genetic interaction between the two proteins. Deletion of KMT2A causes the loss of stem cell properties of tumorigenic organoids, characterized by the differentiation phenotype and reduced expression of LGR5, as confirmed by recent work ( 52 ). The transcriptional profile of KMT2A-ablated CRC cells also indicates a marked down-regulation of stem cell markers [LGR5 and achaete scute-like 2 (ASCL2)] and a concurrent up-regulation of epithelial differentiation markers (KRT20, KRT19, carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1), and CDKN1A).…”

High Yap and Mll1 promote a persistent regenerative cell state induced by Notch signaling and loss of p53

“…Elevated H3K4me3 methylation and transcriptional activity has been correlated to Yap (40)(41)(42). Since the histone methyltransferase Mll1 has been shown to take part in reprogramming processes (43)(44)(45), and we have recently demonstrated a role of Mll1 and H3K4me3 in conferring a cancer stem cell fate in salivary gland and colon tumors (46,47), we investigated whether Mll1 is involved in the regenerative cell state of NICD/p53 −/− organoids. In the small intestinal epithelium we detected pronounced H3K4me3 in the crypt cell compartment (Fig.…”

“…While the role of Yap in cancer is well established (15), the implication of Mll1 and histone modifiers in colon cancer is an emerging field of research (47). Recent experiments in cell cultures and in xenografted tumor cells showed that Mll1 is crucial in solid cancer cells (62)(63)(64).…”

“…Recent experiments in cell cultures and in xenografted tumor cells showed that Mll1 is crucial in solid cancer cells (62)(63)(64). We had previously shown that genetic and pharmacological inhibition of Mll1 in mouse salivary gland, human head and neck cancer, and a Wnt-dependent intestinal cancer model prevented tumor formation (46,47). In leukemia, inhibition of Mll1 and other chromatin modifiers is effective as a treatment option (65,66).…”

Epigenetic Regulation of the Wnt/β-Catenin Signaling Pathway in Cancer

“…Spindlin1 is expressed in Lgr5 + intestinal stem cells and is required for self-renewal. It also promotes cancer stemness in a β-catenin-dependent manner ( Su et al, 2014 ; Grinat et al, 2020 ). Previously, a report had shown that the MLL1/CBP/β-catenin complex promotes tumor initiation and metastasis in the head and neck squamous cell carcinoma by increasing the activation associated mark H3K4me3 at the promoters of target genes ( Qiang et al, 2016 ).…”