Mechanisms of the switch of stem cells to cancer stem cells in head and neck cancer
Final Report Abstract
In this grant period, we provide mechanistic evidence that the histone methyl transferase Mll1 is the key enzyme that controls the epigenetic fate of salivary gland cancer in mice and head and neck cancer in general. The Results on the genetic ablation of Mll1 in salivary gland tumors and the inhibition by small molecules of binding partners on the self-renewal of cancer stem cells are not published. Because of this major new findings, mayor rearrangements of goals in the course of our experimentation were required. Our main results are the following: 1) The data show that the β-catenin-CBP-Mll1-interfering substance ICG-001 elicits changes in H3K4 trimethylation at target gene promoters, and that the epigenetic changes precede transcriptional changes. 2) The data show that nuclear Mll1 and the expression of the stem cell‐associated gene signatures are dependent on the presence of high Wnt/β-catenin signals. 3) The data suggest that in both, murine and human tumors, the β-catenin/CBP/Mll1 axis drives self-renewal and fends off differentiation of cancer stem cells via epigenetic mechanisms. 4) Triple conditional mutant mice were generated, following preparation of chromosome 9, which contains both loxed Mll1 and β-catenin. Remarkably, triple mutant mice did not develop tumors and survived for 150 days. Further evidence indicated that deletion of Mll1 induced differentiation of cancer stem cells. 5) We then examined the potential of available Mll1 and Wnt inhibitors for blocking the self-renewal of mouse salivary gland and human head and neck cancer stem cells. MI2, JQ1, ICG-001 and LF3 inhibited the self-renewal, but C646 did not. Collectively, we provide evidence that β-catenin activation leads to an induction and stabilization of Mll1, and that the β-catenin-CBP interaction with Mll1 is required to trigger H3K4 trimethylation at promoters of self-renewal genes in cancer stem cells. Mll1 thus represents the crucial epigenetic modifier of Wnt/β-catenin signaling of head and neck cancer. Our findings suggest new therapeutic possibilities to treat these dangerous diseases, and they also allow the directed search of target genes that act downstream of Mll1.
Publications
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Wnt/β-catenin signalling induces MLL to create epigenetic changes in salivary gland tumours. EMBO J. 32, 1977-1989, 2013
Wend P, Fang L, Zhu Q, Schipper JH, Loddenkemper C, Kosel F, Brinkmann V, Eckert K, Hindersin S, Holland JD, Lehr S, Kahn M, Ziebold U, Birchmeier W
