Menin and Daxx Interact to Control Neuroendocrine Tumors via Epigenetic Regulation of Membrane Metallo-Endopeptidase.

Neuroendocrine tumors (NETs) often harbor loss-of-function mutations in the MEN1 gene that encodes the protein menin as well as in the Daxx gene. Both menin and Daxx interact with several partners to regulate cellular processes and gene expression. Here, we show that menin directly interacts with Daxx to suppress proliferation of NET cells partly by inhibiting a common target gene, membrane metallo-endopeptidase (Mme). Menin and Daxx are required for each other to enhance histone H3 lysine9 trimethylation (H3K9me3) at Mme promoter, partly through SUV39H1. T429K mutant, a tumor syndrome-causing mutation, abolishes menin's ability to bind to Daxx and in repressing Mme expression and the proliferation of NET cells. Inhibition of Mme in NET cells represses tumor growth in vivo. Our findings unravel a previously unappreciated crosstalk between two crucial proteins that were thought to work via independent pathways, menin and Daxx, by epigenetically suppressing Mme, a potential target to treat NETs.