Protein arginine methyltransferase 3 enhances chemoresistance in pancreatic cancer by methylating hnRNPA1 to increase ABCG2 expression

Ming Chuan Hsu, Mei Ren Pan, Pei Yi Chu, Ya Li Tsai, Chia Hua Tsai, Yan-Shen Shan, Li Tzong Chen, Wen Chun Hung

Research output: Contribution to journalArticle

4 Citations (Scopus)

Abstract

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.

Original languageEnglish
Article number8
JournalCancers
Volume11
Issue number1
DOIs
Publication statusPublished - 2019 Jan 1

Fingerprint

Protein-Arginine N-Methyltransferases
Pancreatic Neoplasms
gemcitabine
Adenosine Triphosphate
Drug Resistance
Methylation
RNA Stability
Epigenomics

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

Cite this

Hsu, Ming Chuan ; Pan, Mei Ren ; Chu, Pei Yi ; Tsai, Ya Li ; Tsai, Chia Hua ; Shan, Yan-Shen ; Chen, Li Tzong ; Hung, Wen Chun. / Protein arginine methyltransferase 3 enhances chemoresistance in pancreatic cancer by methylating hnRNPA1 to increase ABCG2 expression. In: Cancers. 2019 ; Vol. 11, No. 1.
@article{c4cce8e93db2479ebb864f07097999e4,
title = "Protein arginine methyltransferase 3 enhances chemoresistance in pancreatic cancer by methylating hnRNPA1 to increase ABCG2 expression",
abstract = "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.",
author = "Hsu, {Ming Chuan} and Pan, {Mei Ren} and Chu, {Pei Yi} and Tsai, {Ya Li} and Tsai, {Chia Hua} and Yan-Shen Shan and Chen, {Li Tzong} and Hung, {Wen Chun}",
year = "2019",
month = "1",
day = "1",
doi = "10.3390/cancers11010008",
language = "English",
volume = "11",
journal = "Cancers",
issn = "2072-6694",
publisher = "Multidisciplinary Digital Publishing Institute (MDPI)",
number = "1",

}

Protein arginine methyltransferase 3 enhances chemoresistance in pancreatic cancer by methylating hnRNPA1 to increase ABCG2 expression. / Hsu, Ming Chuan; Pan, Mei Ren; Chu, Pei Yi; Tsai, Ya Li; Tsai, Chia Hua; Shan, Yan-Shen; Chen, Li Tzong; Hung, Wen Chun.

In: Cancers, Vol. 11, No. 1, 8, 01.01.2019.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Protein arginine methyltransferase 3 enhances chemoresistance in pancreatic cancer by methylating hnRNPA1 to increase ABCG2 expression

AU - Hsu, Ming Chuan

AU - Pan, Mei Ren

AU - Chu, Pei Yi

AU - Tsai, Ya Li

AU - Tsai, Chia Hua

AU - Shan, Yan-Shen

AU - Chen, Li Tzong

AU - Hung, Wen Chun

PY - 2019/1/1

Y1 - 2019/1/1

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85061917873&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85061917873&partnerID=8YFLogxK

U2 - 10.3390/cancers11010008

DO - 10.3390/cancers11010008

M3 - Article

AN - SCOPUS:85061917873

VL - 11

JO - Cancers

JF - Cancers

SN - 2072-6694

IS - 1

M1 - 8

ER -