Protein Arginine Methyltransferase 3 Enhances Chemoresistance in Pancreatic Cancer by Methylating hnRNPA1 to Increase ABCG2 Expression
Pancreatic cancer is poorly responsive to chemotherapy due to intrinsic or acquired resistance. Our previous study showed that epigenetic modifying enzymes including protein arginine methyltransferase 3 (PRMT3) are dysregulated in gemcitabine (GEM)-resistant pancreatic cancer cells. Here, we attempt...
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doaj-49bc1cac74a84910b4287fb069426adc2020-11-24T20:42:46ZengMDPI AGCancers2072-66942018-12-01111810.3390/cancers11010008cancers11010008Protein Arginine Methyltransferase 3 Enhances Chemoresistance in Pancreatic Cancer by Methylating hnRNPA1 to Increase ABCG2 ExpressionMing-Chuan Hsu0Mei-Ren Pan1Pei-Yi Chu2Ya-Li Tsai3Chia-Hua Tsai4Yan-Shen Shan5Li-Tzong Chen6Wen-Chun Hung7National Institute of Cancer Research, National Health Research Institutes, Tainan 704, TaiwanGraduate Institute of Clinical Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 807, TaiwanDepartment of Pathology, Show Chwan Memorial Hospital, Changhua City 500, TaiwanNational Institute of Cancer Research, National Health Research Institutes, Tainan 704, TaiwanNational Institute of Cancer Research, National Health Research Institutes, Tainan 704, TaiwanDepartment of Surgery, National Cheng Kung University Hospital, Tainan 704, TaiwanNational Institute of Cancer Research, National Health Research Institutes, Tainan 704, TaiwanNational Institute of Cancer Research, National Health Research Institutes, Tainan 704, TaiwanPancreatic cancer is poorly responsive to chemotherapy due to intrinsic or acquired resistance. Our previous study showed that epigenetic modifying enzymes including protein arginine methyltransferase 3 (PRMT3) are dysregulated in gemcitabine (GEM)-resistant pancreatic cancer cells. Here, we attempt to elucidate the role of PRMT3 in chemoresistance. Overexpression of PRMT3 led to increased resistance to GEM in pancreatic cancer cells, whereas reduction of PRMT3 restored GEM sensitivity in resistant cells. We identified a novel PRMT3 target, ATP-binding cassette subfamily G member 2 (ABCG2), which is known to play a critical role in drug resistance. PRMT3 overexpression upregulated ABCG2 expression by increasing its mRNA stability. Mass spectrometric analysis identified hnRNPA1 as a PRMT3 interacting protein, and methylation of hnRNPA1 at R31 by PRMT3 in vivo and in vitro. The expression of methylation-deficient hnRNPA1-R31K mutant reduced the RNA binding activity of hnRNPA1 and the expression of ABCG2 mRNA. Taken together, this provides the first evidence that PRMT3 methylates the RNA recognition motif (RRM) of hnRNPA1 and promotes the binding between hnRNPA1 and ABCG2 to enhance drug resistance. Inhibition of PRMT3 could be a novel strategy for the treatment of GEM-resistant pancreatic cancer.https://www.mdpi.com/2072-6694/11/1/8PRMT3hnRNP A1ABCG2RRMdrug resistance |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Ming-Chuan Hsu Mei-Ren Pan Pei-Yi Chu Ya-Li Tsai Chia-Hua Tsai Yan-Shen Shan Li-Tzong Chen Wen-Chun Hung |
spellingShingle |
Ming-Chuan Hsu Mei-Ren Pan Pei-Yi Chu Ya-Li Tsai Chia-Hua Tsai Yan-Shen Shan Li-Tzong Chen Wen-Chun Hung Protein Arginine Methyltransferase 3 Enhances Chemoresistance in Pancreatic Cancer by Methylating hnRNPA1 to Increase ABCG2 Expression Cancers PRMT3 hnRNP A1 ABCG2 RRM drug resistance |
author_facet |
Ming-Chuan Hsu Mei-Ren Pan Pei-Yi Chu Ya-Li Tsai Chia-Hua Tsai Yan-Shen Shan Li-Tzong Chen Wen-Chun Hung |
author_sort |
Ming-Chuan Hsu |
title |
Protein Arginine Methyltransferase 3 Enhances Chemoresistance in Pancreatic Cancer by Methylating hnRNPA1 to Increase ABCG2 Expression |
title_short |
Protein Arginine Methyltransferase 3 Enhances Chemoresistance in Pancreatic Cancer by Methylating hnRNPA1 to Increase ABCG2 Expression |
title_full |
Protein Arginine Methyltransferase 3 Enhances Chemoresistance in Pancreatic Cancer by Methylating hnRNPA1 to Increase ABCG2 Expression |
title_fullStr |
Protein Arginine Methyltransferase 3 Enhances Chemoresistance in Pancreatic Cancer by Methylating hnRNPA1 to Increase ABCG2 Expression |
title_full_unstemmed |
Protein Arginine Methyltransferase 3 Enhances Chemoresistance in Pancreatic Cancer by Methylating hnRNPA1 to Increase ABCG2 Expression |
title_sort |
protein arginine methyltransferase 3 enhances chemoresistance in pancreatic cancer by methylating hnrnpa1 to increase abcg2 expression |
publisher |
MDPI AG |
series |
Cancers |
issn |
2072-6694 |
publishDate |
2018-12-01 |
description |
Pancreatic cancer is poorly responsive to chemotherapy due to intrinsic or acquired resistance. Our previous study showed that epigenetic modifying enzymes including protein arginine methyltransferase 3 (PRMT3) are dysregulated in gemcitabine (GEM)-resistant pancreatic cancer cells. Here, we attempt to elucidate the role of PRMT3 in chemoresistance. Overexpression of PRMT3 led to increased resistance to GEM in pancreatic cancer cells, whereas reduction of PRMT3 restored GEM sensitivity in resistant cells. We identified a novel PRMT3 target, ATP-binding cassette subfamily G member 2 (ABCG2), which is known to play a critical role in drug resistance. PRMT3 overexpression upregulated ABCG2 expression by increasing its mRNA stability. Mass spectrometric analysis identified hnRNPA1 as a PRMT3 interacting protein, and methylation of hnRNPA1 at R31 by PRMT3 in vivo and in vitro. The expression of methylation-deficient hnRNPA1-R31K mutant reduced the RNA binding activity of hnRNPA1 and the expression of ABCG2 mRNA. Taken together, this provides the first evidence that PRMT3 methylates the RNA recognition motif (RRM) of hnRNPA1 and promotes the binding between hnRNPA1 and ABCG2 to enhance drug resistance. Inhibition of PRMT3 could be a novel strategy for the treatment of GEM-resistant pancreatic cancer. |
topic |
PRMT3 hnRNP A1 ABCG2 RRM drug resistance |
url |
https://www.mdpi.com/2072-6694/11/1/8 |
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