title: Oncogenic Functions of Gli1 in Pancreatic Adenocarcinoma Are Supported by Its PRMT1-Mediated Methylation.
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.
authors.affiliation: Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.|Institute of Pathology and Southwest Cancer Center, Southwest Hospital, Third Military Medical University, Chongqing, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Jung-Mao
authors.initials: JM
authors.lastname: Hsu
authors.affiliation: Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Ya'an
authors.initials: Y
authors.lastname: Kang
authors.affiliation: Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Yongkun
authors.initials: Y
authors.lastname: Wei
authors.affiliation: Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Pei-Chih
authors.initials: PC
authors.lastname: Lee
authors.affiliation: Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.|Department of Obstetrics and Gynecology, Hsinchu Mackay Memorial Hospital, Hsinchu, Taiwan.
authors.forename: Shing-Jyh
authors.initials: SJ
authors.lastname: Chang
authors.affiliation: Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Yi-Hsin
authors.initials: YH
authors.lastname: Hsu
authors.affiliation: Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Hsu
authors.affiliation: Center for Molecular Medicine and Graduate Institute of Cancer Biology, China Medical University, Taichung, Taiwan.
authors.forename: Hung-Ling
authors.initials: HL
authors.lastname: Wang
authors.affiliation: Center for Molecular Medicine and Graduate Institute of Cancer Biology, China Medical University, Taichung, Taiwan.|Genomics Research Center, Academia Sinica, Taipei, Taiwan.
authors.forename: Wei-Chao
authors.initials: WC
authors.lastname: Chang
authors.affiliation: Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Chia-Wei
authors.initials: CW
authors.lastname: Li
authors.affiliation: Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.|The University of Texas Graduate School of Biomedical Sciences at Houston, Houston, Texas.
authors.forename: Hsin-Wei
authors.initials: HW
authors.lastname: Liao
authors.affiliation: Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.|The University of Texas Graduate School of Biomedical Sciences at Houston, Houston, Texas.
authors.forename: Shih-Shin
authors.initials: SS
authors.lastname: Chang
authors.affiliation: Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Weiya
authors.initials: W
authors.lastname: Xia
authors.affiliation: Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.|The University of Texas Graduate School of Biomedical Sciences at Houston, Houston, Texas.
authors.forename: How-Wen
authors.initials: HW
authors.lastname: Ko
authors.affiliation: Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Chao-Kai
authors.initials: CK
authors.lastname: Chou
authors.affiliation: Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Jason B
authors.initials: JB
authors.lastname: Fleming
authors.affiliation: Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Huamin
authors.initials: H
authors.lastname: Wang
authors.affiliation: Department of Breast Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Rosa F
authors.initials: RF
authors.lastname: Hwang
authors.affiliation: Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, Texas.
authors.forename: Yue
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, Texas.
authors.forename: Jun
authors.initials: J
authors.lastname: Qin
authors.affiliation: Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas. mhung@mdanderson.org.|Center for Molecular Medicine and Graduate Institute of Cancer Biology, China Medical University, Taichung, Taiwan.|The University of Texas Graduate School of Biomedical Sciences at Houston, Houston, Texas.|Department of Biotechnology, Asia University, Taichung, Taiwan.
authors.forename: Mien-Chie
authors.initials: MC
authors.lastname: Hung
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics* / Q000473:pathology; D063646:Carcinogenesis / Q000235:genetics*; D006801:Humans; D008745:Methylation; D010190:Pancreatic Neoplasms / Q000235:genetics* / Q000473:pathology; D015398:Signal Transduction; D014162:Transfection; D000071676:Zinc Finger Protein GLI1 / Q000235:genetics* / Q000378:metabolism
chemical_list: C400551:GLI1 protein, human; D000071676:Zinc Finger Protein GLI1