Menin Epigenetically Represses Hedgehog Signaling in MEN1 Tumor Syndrome

Abstract

Multiple endocrine neoplasia type 1 (MEN1) is an inherited tumor syndrome that includes susceptibility to pancreatic islet tumors. This syndrome results from mutations in the MEN1 gene, encoding menin. Menin acts as an oncogenic co-factor for MLL-fusion protein-mediated histone H3 lysine 4 methylation, but the precise basis for how menin suppresses gene expression and proliferation of pancreatic beta cells remains poorly understood. Here we show that menin ablation enhances Hedgehog (Hh) signaling, a pro-proliferative and oncogenic pathway, in murine pancreatic islets. Menin directly interacts with protein arginine methyltransferase 5 (PRMT5), a negative regulator of gene transcription. Menin recruits PRMT5 to the promoter of the Gas1 gene, a crucial factor for binding of Sonic hedgehog (Shh) ligand to its receptor PTCH1 and subsequent activation of the Hh signaling pathway, increases repressive histone arginine dimethylation (H4R3m2s) and suppresses Gas1 expression. Notably, MEN1 disease-related menin mutants have reduced binding to PRMT5, and fail to impart the repressive H4R3m2s mark at the Gas1 promoter, resulting in its elevated expression. Pharmacological inhibition of Hh signaling significantly reduces proliferation of insulinoma cells, and expression of Hh signaling targets including Ptch1, in MEN1 tumors of mice. These findings uncover a novel link between menin and Hh signaling whereby menin/PRMT5 epigenetically suppress Hh signaling, revealing it as a target for treating MEN1 tumors.

Menin Is Required for Optimal Processing of the MicroRNA let-7a

“…The gene mutated in this syndrome, MEN1, encodes a nuclear protein of 610 amino acids, menin (5,6). Menin interacts with multiple proteins and is involved in a variety of cellular processes including gene transcription, cell proliferation, apoptosis, and genome stability (7)(8)(9)(10)(11)(12), but the precise mechanisms regarding menin-mediated suppression of cell proliferation remain to be elucidated. The recently solved crystal structure of menin reveals that it contains a deep pocket that binds short MLL1 or JunD peptides in the same manner, but has opposite effects on gene transcription (13), supporting the capacity of menin to act as either a contextdependent transcription activator or repressor.…”

PTCH 1 staining of pancreatic neuroendocrine tumor (PNET) samples from patients with and without multiple endocrine neoplasia (MEN-1) syndrome reveals a potential therapeutic target

“…11 Moreover, by pharmacologically inhibiting the HH signaling pathway with a HH antagonist, GDC-0449, we significantly suppressed MEN-1 tumor development. 11 This pathway is potentially targetable in PNET patients as GDC-0449 (Vismodegib, Erivedge) is currently available clinically for the treatment of basal cell carcinoma.…”

“…11 Moreover, by pharmacologically inhibiting the HH signaling pathway with a HH antagonist, GDC-0449, we significantly suppressed MEN-1 tumor development. 11 This pathway is potentially targetable in PNET patients as GDC-0449 (Vismodegib, Erivedge) is currently available clinically for the treatment of basal cell carcinoma. 12 Vismodegib (Genentech, South San Francisco, California) acts by selectively binding to Smoothened (SMO), a 7-helix transmembrane receptor, thereby inhibiting activation of transcription factors of the glioma-associated oncogene family, to suppress tumor proliferation and growth.…”

“…12,13 Activation of this pathway can be demonstrated by immunohistochemistry (IHC) staining for protein patched homolog 1 (PTCH1), the receptor for sonic hedgehog ligand and also a target gene upregulated by HH signaling. [11][12][13] The aims of the current study were to 1) identify whether the same HH pathway abnormalities we previously demonstrated in mice were also present in human fresh and archival PNET specimens by IHC PTCH 1 staining, 2) to compare HH pathway IHC staining patterns in PNET specimens from MEN-1-associated and sporadic disease patients, and 3) to evaluate clinical features of patients that might predict the presence of HH pathway abnormalities in PNET patients. Our ultimate goal is to examine whether HH pathway inhibitors may play a role in mediating disease outcome for PNET patients.…”

Molecular challenges of neuroendocrine tumors (Review)

“…Tumor suppressors, menin and Daxx, reported to suppress NETs by interacting with each other and epigenetically inhibiting a pro-proliferative gene in endocrine tumors, Mme, via enhancing H3K9me3 modification. MEN1 can interact with histone deacethylases (HDACs) and histone methyltransferases including PRMT5 and SUV39H1, and depending on that act either as activator or supressor of gene transcriptional activity (124)(125)(126)(127). Menins role as the regulators in Hox gene expression was well documented (128,129).…”