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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
- 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.
- Subjects :
- 0301 basic medicine
Cancer Research
endocrine system diseases
Carcinogenesis
Adenocarcinoma
Transfection
Methylation
Zinc Finger Protein GLI1
Article
03 medical and health sciences
GLI1
Humans
Hedgehog
Transcription factor
integumentary system
biology
Effector
Promoter
digestive system diseases
Pancreatic Neoplasms
030104 developmental biology
Oncology
biology.protein
Cancer research
Signal transduction
Signal Transduction
Subjects
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