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

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

Authors :
Hung Ling Wang
Chia Wei Li
Jennifer L. Hsu
Rosa F. Hwang
Yue Chen
Ya'an Kang
Chao Kai Chou
Huamin Wang
Yan Wang
Jason B. Fleming
Yi Hsin Hsu
Shih Shin Chang
Weiya Xia
Jun Qin
Mien Chie Hung
Pei-Chih Lee
Hsin Wei Liao
Jung Mao Hsu
Yongkun Wei
How Wen Ko
Shing-Jyh Chang
Wei Chao Chang
Source :
Cancer Research. 76:7049-7058
Publication Year :
2016
Publisher :
American Association for Cancer Research (AACR), 2016.

Abstract

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.

Details

ISSN :
15387445 and 00085472
Volume :
76
Database :
OpenAIRE
Journal :
Cancer Research
Accession number :
edsair.doi.dedup.....d0fa248e6b87c584de8b60793013e28d
Full Text :
https://doi.org/10.1158/0008-5472.can-16-0715