PRMT1-dependent regulation of RNA metabolism and DNA damage response sustains pancreatic ductal adenocarcinoma

Virginia Giuliani; Meredith A. Miller; Chiu Yi Liu; Stella R. Hartono; Caleb A. Class; Christopher A. Bristow; Erika Suzuki; Lionel A. Sanz; Guang Gao; Jason P. Gay; Ningping Feng; Johnathon L. Rose; Hideo Tomihara; Joseph R. Daniele; Michael D. Peoples; Jennifer P. Bardenhagen; Mary K. Geck Do; Qing E. Chang; Bhavatarini Vangamudi; Christopher Vellano; Haoqiang Ying; Angela K. Deem; Kim Anh Do; Giannicola Genovese; Joseph R. Marszalek; Jeffrey J. Kovacs; Michael Kim; Jason B. Fleming; Ernesto Guccione; Andrea Viale; Anirban Maitra; M. Emilia Di Francesco; Timothy A. Yap; Philip Jones; Giulio Draetta; Alessandro Carugo; Frederic Chedin; Timothy P. Heffernan

doi:10.1038/s41467-021-24798-y

PRMT1-dependent regulation of RNA metabolism and DNA damage response sustains pancreatic ductal adenocarcinoma

Virginia Giuliani, Meredith A. Miller, Chiu Yi Liu, Stella R. Hartono, Caleb A. Class, Christopher A. Bristow, Erika Suzuki, Lionel A. Sanz, Guang Gao, Jason P. Gay, Ningping Feng, Johnathon L. Rose, Hideo Tomihara, Joseph R. Daniele, Michael D. Peoples, Jennifer P. Bardenhagen, Mary K. Geck Do, Qing E. Chang, Bhavatarini Vangamudi, Christopher VellanoHaoqiang Ying, Angela K. Deem, Kim Anh Do, Giannicola Genovese, Joseph R. Marszalek, Jeffrey J. Kovacs, Michael Kim, Jason B. Fleming, Ernesto Guccione, Andrea Viale, Anirban Maitra, M. Emilia Di Francesco, Timothy A. Yap, Philip Jones, Giulio Draetta, Alessandro Carugo, Frederic Chedin, Timothy P. Heffernan

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26 Scopus citations

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive cancer that has remained clinically challenging to manage. Here we employ an RNAi-based in vivo functional genomics platform to determine epigenetic vulnerabilities across a panel of patient-derived PDAC models. Through this, we identify protein arginine methyltransferase 1 (PRMT1) as a critical dependency required for PDAC maintenance. Genetic and pharmacological studies validate the role of PRMT1 in maintaining PDAC growth. Mechanistically, using proteomic and transcriptomic analyses, we demonstrate that global inhibition of asymmetric arginine methylation impairs RNA metabolism, which includes RNA splicing, alternative polyadenylation, and transcription termination. This triggers a robust downregulation of multiple pathways involved in the DNA damage response, thereby promoting genomic instability and inhibiting tumor growth. Taken together, our data support PRMT1 as a compelling target in PDAC and informs a mechanism-based translational strategy for future therapeutic development. Statement of significance PDAC is a highly lethal cancer with limited therapeutic options. This study identified and characterized PRMT1-dependent regulation of RNA metabolism and coordination of key cellular processes required for PDAC tumor growth, defining a mechanism-based translational hypothesis for PRMT1 inhibitors.

Original language	English (US)
Article number	4626
Journal	Nature communications
Volume	12
Issue number	1
DOIs	https://doi.org/10.1038/s41467-021-24798-y
State	Published - Dec 1 2021

ASJC Scopus subject areas

General Chemistry
General Biochemistry, Genetics and Molecular Biology
General Physics and Astronomy

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Giuliani, V., Miller, M. A., Liu, C. Y., Hartono, S. R., Class, C. A., Bristow, C. A., Suzuki, E., Sanz, L. A., Gao, G., Gay, J. P., Feng, N., Rose, J. L., Tomihara, H., Daniele, J. R., Peoples, M. D., Bardenhagen, J. P., Geck Do, M. K., Chang, Q. E., Vangamudi, B., ... Heffernan, T. P. (2021). PRMT1-dependent regulation of RNA metabolism and DNA damage response sustains pancreatic ductal adenocarcinoma. Nature communications, 12(1), Article 4626. https://doi.org/10.1038/s41467-021-24798-y

Giuliani, V, Miller, MA, Liu, CY, Hartono, SR, Class, CA, Bristow, CA , Suzuki, E, Sanz, LA, Gao, G, Gay, JP, Feng, N , Rose, JL, Tomihara, H, Daniele, JR, Peoples, MD, Bardenhagen, JP, Geck Do, MK, Chang, QE, Vangamudi, B, Vellano, C, Ying, H, Deem, AK, Do, KA , Genovese, G, Marszalek, JR, Kovacs, JJ, Kim, M, Fleming, JB, Guccione, E, Viale, A , Maitra, A, Emilia Di Francesco, M, Yap, TA, Jones, P, Draetta, G, Carugo, A, Chedin, F & Heffernan, TP 2021, 'PRMT1-dependent regulation of RNA metabolism and DNA damage response sustains pancreatic ductal adenocarcinoma', Nature communications, vol. 12, no. 1, 4626. https://doi.org/10.1038/s41467-021-24798-y

@article{7b479de622c34bfcb25819be196cfe8c,

title = "PRMT1-dependent regulation of RNA metabolism and DNA damage response sustains pancreatic ductal adenocarcinoma",

abstract = "Pancreatic ductal adenocarcinoma (PDAC) is an aggressive cancer that has remained clinically challenging to manage. Here we employ an RNAi-based in vivo functional genomics platform to determine epigenetic vulnerabilities across a panel of patient-derived PDAC models. Through this, we identify protein arginine methyltransferase 1 (PRMT1) as a critical dependency required for PDAC maintenance. Genetic and pharmacological studies validate the role of PRMT1 in maintaining PDAC growth. Mechanistically, using proteomic and transcriptomic analyses, we demonstrate that global inhibition of asymmetric arginine methylation impairs RNA metabolism, which includes RNA splicing, alternative polyadenylation, and transcription termination. This triggers a robust downregulation of multiple pathways involved in the DNA damage response, thereby promoting genomic instability and inhibiting tumor growth. Taken together, our data support PRMT1 as a compelling target in PDAC and informs a mechanism-based translational strategy for future therapeutic development. Statement of significance PDAC is a highly lethal cancer with limited therapeutic options. This study identified and characterized PRMT1-dependent regulation of RNA metabolism and coordination of key cellular processes required for PDAC tumor growth, defining a mechanism-based translational hypothesis for PRMT1 inhibitors.",

author = "Virginia Giuliani and Miller, {Meredith A.} and Liu, {Chiu Yi} and Hartono, {Stella R.} and Class, {Caleb A.} and Bristow, {Christopher A.} and Erika Suzuki and Sanz, {Lionel A.} and Guang Gao and Gay, {Jason P.} and Ningping Feng and Rose, {Johnathon L.} and Hideo Tomihara and Daniele, {Joseph R.} and Peoples, {Michael D.} and Bardenhagen, {Jennifer P.} and {Geck Do}, {Mary K.} and Chang, {Qing E.} and Bhavatarini Vangamudi and Christopher Vellano and Haoqiang Ying and Deem, {Angela K.} and Do, {Kim Anh} and Giannicola Genovese and Marszalek, {Joseph R.} and Kovacs, {Jeffrey J.} and Michael Kim and Fleming, {Jason B.} and Ernesto Guccione and Andrea Viale and Anirban Maitra and {Emilia Di Francesco}, M. and Yap, {Timothy A.} and Philip Jones and Giulio Draetta and Alessandro Carugo and Frederic Chedin and Heffernan, {Timothy P.}",

note = "Publisher Copyright: {\textcopyright} 2021, The Author(s).",

year = "2021",

month = dec,

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doi = "10.1038/s41467-021-24798-y",

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T1 - PRMT1-dependent regulation of RNA metabolism and DNA damage response sustains pancreatic ductal adenocarcinoma

AU - Giuliani, Virginia

AU - Miller, Meredith A.

AU - Liu, Chiu Yi

AU - Hartono, Stella R.

AU - Class, Caleb A.

AU - Bristow, Christopher A.

AU - Suzuki, Erika

AU - Sanz, Lionel A.

AU - Gao, Guang

AU - Gay, Jason P.

AU - Feng, Ningping

AU - Rose, Johnathon L.

AU - Tomihara, Hideo

AU - Daniele, Joseph R.

AU - Peoples, Michael D.

AU - Bardenhagen, Jennifer P.

AU - Geck Do, Mary K.

AU - Chang, Qing E.

AU - Vangamudi, Bhavatarini

AU - Vellano, Christopher

AU - Ying, Haoqiang

AU - Deem, Angela K.

AU - Do, Kim Anh

AU - Genovese, Giannicola

AU - Marszalek, Joseph R.

AU - Kovacs, Jeffrey J.

AU - Kim, Michael

AU - Fleming, Jason B.

AU - Guccione, Ernesto

AU - Viale, Andrea

AU - Maitra, Anirban

AU - Emilia Di Francesco, M.

AU - Yap, Timothy A.

AU - Jones, Philip

AU - Draetta, Giulio

AU - Carugo, Alessandro

AU - Chedin, Frederic

AU - Heffernan, Timothy P.

PY - 2021/12/1

Y1 - 2021/12/1

N2 - Pancreatic ductal adenocarcinoma (PDAC) is an aggressive cancer that has remained clinically challenging to manage. Here we employ an RNAi-based in vivo functional genomics platform to determine epigenetic vulnerabilities across a panel of patient-derived PDAC models. Through this, we identify protein arginine methyltransferase 1 (PRMT1) as a critical dependency required for PDAC maintenance. Genetic and pharmacological studies validate the role of PRMT1 in maintaining PDAC growth. Mechanistically, using proteomic and transcriptomic analyses, we demonstrate that global inhibition of asymmetric arginine methylation impairs RNA metabolism, which includes RNA splicing, alternative polyadenylation, and transcription termination. This triggers a robust downregulation of multiple pathways involved in the DNA damage response, thereby promoting genomic instability and inhibiting tumor growth. Taken together, our data support PRMT1 as a compelling target in PDAC and informs a mechanism-based translational strategy for future therapeutic development. Statement of significance PDAC is a highly lethal cancer with limited therapeutic options. This study identified and characterized PRMT1-dependent regulation of RNA metabolism and coordination of key cellular processes required for PDAC tumor growth, defining a mechanism-based translational hypothesis for PRMT1 inhibitors.

AB - Pancreatic ductal adenocarcinoma (PDAC) is an aggressive cancer that has remained clinically challenging to manage. Here we employ an RNAi-based in vivo functional genomics platform to determine epigenetic vulnerabilities across a panel of patient-derived PDAC models. Through this, we identify protein arginine methyltransferase 1 (PRMT1) as a critical dependency required for PDAC maintenance. Genetic and pharmacological studies validate the role of PRMT1 in maintaining PDAC growth. Mechanistically, using proteomic and transcriptomic analyses, we demonstrate that global inhibition of asymmetric arginine methylation impairs RNA metabolism, which includes RNA splicing, alternative polyadenylation, and transcription termination. This triggers a robust downregulation of multiple pathways involved in the DNA damage response, thereby promoting genomic instability and inhibiting tumor growth. Taken together, our data support PRMT1 as a compelling target in PDAC and informs a mechanism-based translational strategy for future therapeutic development. Statement of significance PDAC is a highly lethal cancer with limited therapeutic options. This study identified and characterized PRMT1-dependent regulation of RNA metabolism and coordination of key cellular processes required for PDAC tumor growth, defining a mechanism-based translational hypothesis for PRMT1 inhibitors.

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U2 - 10.1038/s41467-021-24798-y

DO - 10.1038/s41467-021-24798-y

M3 - Article

C2 - 34330913

AN - SCOPUS:85111617627

SN - 2041-1723

VL - 12

JO - Nature communications

JF - Nature communications

IS - 1

M1 - 4626

ER -

PRMT1-dependent regulation of RNA metabolism and DNA damage response sustains pancreatic ductal adenocarcinoma

Abstract

ASJC Scopus subject areas

MD Anderson CCSG core facilities

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