Oncogenic Functions of Gli1 in Pancreatic Adenocarcinoma Are Supported by Its PRMT1-Mediated Methylation

The oncogenic transcription factor Gli1 is a critical effector in the Hedgehog (Hh) pathway, which is necessary for the development and progression of pancreatic ductal adenocarcinoma (PDAC). Although TGFβ and K-Ras are known regulators of Gli1 gene transcription in this setting, it is not understoo...

Full description

Saved in:
Bibliographic Details
Published in:Cancer research (Chicago, Ill.) Ill.), 2016-12, Vol.76 (23), p.7049-7058
Main Authors: Wang, Yan, Hsu, Jung-Mao, Kang, Ya'an, Wei, Yongkun, Lee, Pei-Chih, Chang, Shing-Jyh, Hsu, Yi-Hsin, Hsu, Jennifer L, Wang, Hung-Ling, Chang, Wei-Chao, Li, Chia-Wei, Liao, Hsin-Wei, Chang, Shih-Shin, Xia, Weiya, Ko, How-Wen, Chou, Chao-Kai, Fleming, Jason B, Wang, Huamin, Hwang, Rosa F, Chen, Yue, Qin, Jun, Hung, Mien-Chie
Format: Article
Language:English
Subjects:
Adenocarcinoma - genetics
Adenocarcinoma - pathology
Carcinogenesis - genetics
Humans
Methylation
Pancreatic Neoplasms
Pancreatic Neoplasms - genetics
Pancreatic Neoplasms - pathology
Signal Transduction
Transfection
Zinc Finger Protein GLI1 - genetics
Zinc Finger Protein GLI1 - metabolism
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:The oncogenic transcription factor Gli1 is a critical effector in the Hedgehog (Hh) pathway, which is necessary for the development and progression of pancreatic ductal adenocarcinoma (PDAC). Although TGFβ and K-Ras are known regulators of Gli1 gene transcription in this setting, it is not understood how Gli1 functional activity is regulated. Here, we report the identification of Gli1 as a substrate for the protein arginine N-methyltransferase PRMT1 in PDAC. We found that PRMT1 methylates Gli1 at R597, promoting its transcriptional activity by enhancing the binding of Gli1 to its target gene promoters. Interruption of Gli1 methylation attenuates oncogenic functions of Gli1 and sensitizes PDAC cells to gemcitabine treatment. In human PDAC specimens, the levels of both total Gli1 and methylated Gli1 were correlated positively with PRMT1 protein levels. Notably, PRMT1 regulated Gli1 independently of the canonical Hh pathway as well as the TGFβ/Kras-mediated noncanonical Hh pathway, thereby signifying a novel regulatory mechanism for Gli1 transcriptional activity. Taken together, our results identified a new posttranslational modification of Gli1 that underlies its pivotal oncogenic functions in PDAC. Cancer Res; 76(23); 7049-58. ©2016 AACR.
ISSN:0008-5472
1538-7445
DOI:10.1158/0008-5472.can-16-0715