PMID- 23580576
OWN - NLM
STAT- MEDLINE
DCOM- 20130612
LR  - 20211021
IS  - 1538-7445 (Electronic)
IS  - 0008-5472 (Print)
IS  - 0008-5472 (Linking)
VI  - 73
IP  - 8
DP  - 2013 Apr 15
TI  - Menin epigenetically represses Hedgehog signaling in MEN1 tumor syndrome.
PG  - 2650-8
LID - 10.1158/0008-5472.CAN-12-3158 [doi]
AB  - 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. Although menin acts as an oncogenic 
      cofactor for mixed lineage leukemia (MLL) fusion protein-mediated histone H3 
      lysine 4 methylation, 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 signaling, a proproliferative 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 Hedgehog signaling pathway, increases repressive 
      histone arginine symmetric 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. Pharmacologic inhibition of Hedgehog 
      signaling significantly reduces proliferation of insulinoma cells, and expression 
      of Hedgehog signaling targets including Ptch1, in MEN1 tumors of mice. These 
      findings uncover a novel link between menin and Hedgehog signaling whereby 
      menin/PRMT5 epigenetically suppresses Hedgehog signaling, revealing it as a 
      target for treating MEN1 tumors.
CI  - (c)2013 AACR.
FAU - Gurung, Buddha
AU  - Gurung B
AD  - Department of Cancer Biology, Abramson Family Cancer Research Institute, Abramson 
      Cancer Center, University of Pennsylvania Perelman School of Medicine, 
      Philadelphia, PA 19104, USA.
FAU - Feng, Zijie
AU  - Feng Z
FAU - Iwamoto, Daniel V
AU  - Iwamoto DV
FAU - Thiel, Austin
AU  - Thiel A
FAU - Jin, Guanghui
AU  - Jin G
FAU - Fan, Chen-Min
AU  - Fan CM
FAU - Ng, Jessica M Y
AU  - Ng JM
FAU - Curran, Tom
AU  - Curran T
FAU - Hua, Xianxin
AU  - Hua X
LA  - eng
GR  - R01-CA-113962/CA/NCI NIH HHS/United States
GR  - R01 DK084963/DK/NIDDK NIH HHS/United States
GR  - R01 CA113962/CA/NCI NIH HHS/United States
GR  - R01-DK085121/DK/NIDDK NIH HHS/United States
GR  - R01 DK097555/DK/NIDDK NIH HHS/United States
GR  - R01 DK085121/DK/NIDDK NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20130411
PL  - United States
TA  - Cancer Res
JT  - Cancer research
JID - 2984705R
RN  - 0 (Anilides)
RN  - 0 (Cell Cycle Proteins)
RN  - 0 (GAS1 protein, human)
RN  - 0 (GPI-Linked Proteins)
RN  - 0 (Hedgehog Proteins)
RN  - 0 (HhAntag691)
RN  - 0 (Histones)
RN  - 0 (MEN1 protein, human)
RN  - 0 (Proto-Oncogene Proteins)
RN  - 0 (Pyridines)
RN  - 0 (Receptors, G-Protein-Coupled)
RN  - 0 (SMO protein, human)
RN  - 0 (Smoothened Receptor)
RN  - EC 2.1.1.319 (PRMT5 protein, human)
RN  - EC 2.1.1.319 (Protein-Arginine N-Methyltransferases)
SB  - IM
MH  - Anilides/pharmacology
MH  - Animals
MH  - Cell Cycle Proteins/genetics/metabolism
MH  - *Epigenesis, Genetic
MH  - GPI-Linked Proteins/genetics/metabolism
MH  - Gene Expression Regulation, Neoplastic
MH  - Hedgehog Proteins/*metabolism
MH  - Histones/metabolism
MH  - Humans
MH  - Islets of Langerhans/metabolism/pathology
MH  - Methylation
MH  - Mice
MH  - Multiple Endocrine Neoplasia Type 1/*genetics/*metabolism
MH  - Promoter Regions, Genetic
MH  - Protein Binding
MH  - Protein-Arginine N-Methyltransferases/genetics/metabolism
MH  - Proto-Oncogene Proteins/*genetics/*metabolism
MH  - Pyridines/pharmacology
MH  - Receptors, G-Protein-Coupled/antagonists & inhibitors
MH  - *Signal Transduction/drug effects
MH  - Smoothened Receptor
PMC - PMC4100916
MID - NIHMS515421
COIS- Conflict of Interest: No conflicts of interests are declared by any of the 
      authors.
EDAT- 2013/04/13 06:00
MHDA- 2013/06/13 06:00
PMCR- 2014/07/16
CRDT- 2013/04/13 06:00
PHST- 2013/04/13 06:00 [entrez]
PHST- 2013/04/13 06:00 [pubmed]
PHST- 2013/06/13 06:00 [medline]
PHST- 2014/07/16 00:00 [pmc-release]
AID - 0008-5472.CAN-12-3158 [pii]
AID - 10.1158/0008-5472.CAN-12-3158 [doi]
PST - ppublish
SO  - Cancer Res. 2013 Apr 15;73(8):2650-8. doi: 10.1158/0008-5472.CAN-12-3158. Epub 
      2013 Apr 11.