PMID- 23928057
OWN - NLM
STAT- MEDLINE
DCOM- 20140528
LR  - 20211021
IS  - 1557-3125 (Electronic)
IS  - 1541-7786 (Print)
IS  - 1541-7786 (Linking)
VI  - 11
IP  - 10
DP  - 2013 Oct
TI  - Menin directly represses Gli1 expression independent of canonical Hedgehog 
      signaling.
PG  - 1215-22
LID - 10.1158/1541-7786.MCR-13-0170 [doi]
AB  - Multiple endocrine neoplasia type 1 (MEN-1), is a familial tumor syndrome 
      resulting from mutations in the tumor suppressor gene menin (MEN1). Menin plays 
      an essential role in both repressing and activating gene expression. However, it 
      is not well understood how menin represses expression of multiple genes. Upon 
      MEN1 excision, the transcription factor Gli1 and its target genes, including 
      Ptch1 and c-Myc, were shown to be elevated in the absence of an apparent 
      Hedgehog) pathway-activating ligand or when Smoothened (SMO), a key component of 
      the pathway, is inhibited. Menin binds to the GLI1 promoter and recruits PRMT5, a 
      histone arginine methyltransferase associated with transcriptional repression. 
      Both PRMT5 binding and histone H4 arginine 3 methylation (H4R3m2s) are decreased 
      at the GLI1 promoter in MEN1-excised cells. Moreover, MEN1 ablation resulted in 
      increased binding of transcriptionally active Gli1 at the GLI1 promoter in a 
      manner not influenced by the canonical Hedgehog signaling pathway. Inhibition of 
      Gli1 by the small-molecule inhibitor GANT-61 led to decreased expression of Gli1 
      and its target genes in MEN1-depeleted cells. Furthermore, GANT-61 potently 
      suppressed proliferation of MEN1-excised cells as compared with control cells. 
      These findings uncover a novel epigenetic link whereby menin directly represses 
      Gli1 expression, independent of the canonical Hedgehog signaling pathway, via 
      PRMT5 and its repressive H4R3m2s mark. IMPLICATIONS: Inhibition of GLI1 
      suppresses neuroendocrine tumors harboring mutations in the MEN1 gene.
FAU - Gurung, Buddha
AU  - Gurung B
AD  - Department of Cancer Biology, Abramson Cancer Center, Abramson Family Cancer 
      Research Institute, University of Pennsylvania Perelman School of Medicine, 421 
      Curie Blvd., Philadelphia, PA 19104. huax@mail.med.upenn.edu.
FAU - Feng, Zijie
AU  - Feng Z
FAU - Hua, Xianxin
AU  - Hua X
LA  - eng
GR  - R01 CA113962/CA/NCI NIH HHS/United States
GR  - R01 DK085121/DK/NIDDK NIH HHS/United States
GR  - R01-DK085121/DK/NIDDK NIH HHS/United States
GR  - R01-CA-113962/CA/NCI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20130808
PL  - United States
TA  - Mol Cancer Res
JT  - Molecular cancer research : MCR
JID - 101150042
RN  - 0 (Cell Cycle Proteins)
RN  - 0 (GANT 61)
RN  - 0 (GPI-Linked Proteins)
RN  - 0 (Gas1 protein, mouse)
RN  - 0 (Hedgehog Proteins)
RN  - 0 (Histones)
RN  - 0 (Men1 protein, mouse)
RN  - 0 (Oncogene Proteins)
RN  - 0 (Proto-Oncogene Proteins)
RN  - 0 (Pyridines)
RN  - 0 (Pyrimidines)
RN  - 0 (Trans-Activators)
RN  - 0 (Zinc Finger Protein GLI1)
RN  - EC 2.1.1.- (Protein Methyltransferases)
RN  - EC 2.1.1.319 (Prmt5 protein, mouse)
RN  - EC 2.1.1.319 (Protein-Arginine N-Methyltransferases)
SB  - IM
MH  - Animals
MH  - Cell Cycle Proteins/genetics/metabolism
MH  - Cells, Cultured
MH  - Epigenesis, Genetic
MH  - Epigenomics
MH  - GPI-Linked Proteins/genetics/metabolism
MH  - Gene Expression Regulation, Neoplastic
MH  - Hedgehog Proteins/*genetics/*metabolism
MH  - Histones/metabolism
MH  - Humans
MH  - Methylation
MH  - Mice
MH  - Mutation
MH  - Oncogene Proteins/*genetics/*metabolism
MH  - Promoter Regions, Genetic
MH  - Protein Binding
MH  - Protein Methyltransferases/genetics/metabolism
MH  - Protein-Arginine N-Methyltransferases
MH  - Proto-Oncogene Proteins/*genetics/*metabolism
MH  - Pyridines/pharmacology
MH  - Pyrimidines/pharmacology
MH  - Signal Transduction/genetics/physiology
MH  - Trans-Activators/*genetics/*metabolism
MH  - Zinc Finger Protein GLI1
PMC - PMC4028077
MID - NIHMS513877
COIS- Conflicts of Interest. The authors declare no conflict of interest.
EDAT- 2013/08/10 06:00
MHDA- 2014/05/29 06:00
PMCR- 2014/10/01
CRDT- 2013/08/10 06:00
PHST- 2013/08/10 06:00 [entrez]
PHST- 2013/08/10 06:00 [pubmed]
PHST- 2014/05/29 06:00 [medline]
PHST- 2014/10/01 00:00 [pmc-release]
AID - 1541-7786.MCR-13-0170 [pii]
AID - 10.1158/1541-7786.MCR-13-0170 [doi]
PST - ppublish
SO  - Mol Cancer Res. 2013 Oct;11(10):1215-22. doi: 10.1158/1541-7786.MCR-13-0170. Epub 
      2013 Aug 8.