Researchers at the Institute for Research in Biomedicine (IRB) in Barcelona, and a team at the Max Delbrück Center for Molecular Medicine (MDC) in the Helmholtz Association in Germany have analyzed clinical data to show that colon cancer patients whose tumors have a large amount of the Mll1 protein have a worse prognosis than patients with tumors that contain little Mll1.
Their study “The epigenetic regulator Mll1 is required for Wnt-driven intestinal tumorigenesis and cancer stemness” appears in Nature Communications.
“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 investigators wrote.
“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.”
The Wnt signaling pathway regulates the self-renewal and division of stem cells. If mutations occur that trigger a more active Wnt signaling cascade, the affected stem cells become more resistant than healthy stem cells. They then multiply uncontrollably and form tumors. Although chemotherapy slows down the cell division, it can also increase the selection pressure on cancer stem cells.
“They become resistant to the treatment and form new tumors that, due to the mutation, grow more rapidly and are even more aggressive,” said Julian Heuberger, PhD, a lead author and head of the study who now works in the division of hepatology and gastroenterology in the medical department of Charité-Universitätsmediz in Berlin. This is why it is so important, he explained, to understand the regulatory mechanisms of cancer stem cells in particular. “With Mll1,” he added, “we have found a molecular switch that primarily controls the self-renewal and division of cancer stem cells in colon cancer.”
Genetically knocking out a gene, as the scientists did with mice, is not possible in humans. In mice, the formation of cancer stem cells can be followed over time and there are always enough stem cells available for experiments. However, MII1 could be blocked with a chemical drug. Small molecules have already been developed for this research, e.g., the inhibitors MI-2 and MM-401, which bind to essential Mll1 complexes and thereby inactivate its function.
Understanding the way these molecules work will enable us to develop and test these and even more clinically effective Mll1 inhibitors,” said Walter Birchmeier, PhD, who runs the signal transduction in development and cancer lab at the MDC and the study’s last author.
Healthy stem cells in the intestine are apparently not blocked in the process.
“We were able to use another system in mice, salivary gland cancer cells, to show that Mll1 only affects cancer cells and not healthy stem cells,” noted Birchmeier, who pointed out that this also provides hope for the treatment of other types of cancer, as animal models have shown that head and neck tumors have the same Achilles’ heel. “On the basis of our mouse studies, clinical trials are currently being conducted at the University Hospital of Düsseldorf to evaluate the use of Mll1 inhibitors in the treatment of head and neck tumors.”
If they are successful, patients with colon cancer could be treated in the future with both chemotherapy and Mll1 inhibitors, i.e., therapeutics that specifically impede cancer stem cells. This increases the chances of a successful treatment, even with advanced colon cancer, say the researchers.
