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Cancer Res. 2017 Sep 15;77(18):5011-5025. doi: 10.1158/0008-5472.CAN-16-2704. Epub 2017 Jul 7.

Posttranscriptional Regulation of PARG mRNA by HuR Facilitates DNA Repair and Resistance to PARP Inhibitors.

Author information

1
Department of Surgery, The Jefferson Pancreas, Biliary and Related Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania.
2
Department of Cancer Biology, Thomas Jefferson University, Philadelphia, Pennsylvania.
3
Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania.
4
Computational Medicine Center, Thomas Jefferson University, Philadelphia, Pennsylvania.
5
Department of Pathology, Thomas Jefferson University, Philadelphia, Pennsylvania.
6
Novartis Institute for Biomedical Research, Basel, Switzerland.
7
Division of Hematology and Oncology, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC.
8
Department of Biochemistry and Molecular Medicine, Université de Montréal, Montréal, Québec, Canada.
9
Department of Surgery, The Jefferson Pancreas, Biliary and Related Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania. jonathan.brody@jefferson.edu.

Abstract

The majority of pancreatic ductal adenocarcinomas (PDAC) rely on the mRNA stability factor HuR (ELAV-L1) to drive cancer growth and progression. Here, we show that CRISPR-Cas9-mediated silencing of the HuR locus increases the relative sensitivity of PDAC cells to PARP inhibitors (PARPi). PDAC cells treated with PARPi stimulated translocation of HuR from the nucleus to the cytoplasm, specifically promoting stabilization of a new target, poly (ADP-ribose) glycohydrolase (PARG) mRNA, by binding a unique sequence embedded in its 3' untranslated region. HuR-dependent upregulation of PARG expression facilitated DNA repair via hydrolysis of polyADP-ribose on related repair proteins. Accordingly, strategies to inhibit HuR directly promoted DNA damage accumulation, inefficient PAR removal, and persistent PARP-1 residency on chromatin (PARP-1 trapping). Immunoprecipitation assays demonstrated that the PARP-1 protein binds and posttranslationally modifies HuR in PARPi-treated PDAC cells. In a mouse xenograft model of human PDAC, PARPi monotherapy combined with targeted silencing of HuR significantly reduced tumor growth compared with PARPi therapy alone. Our results highlight the HuR-PARG axis as an opportunity to enhance PARPi-based therapies. Cancer Res; 77(18); 5011-25. ©2017 AACR.

PMID:
28687616
PMCID:
PMC5663502
DOI:
10.1158/0008-5472.CAN-16-2704
[Indexed for MEDLINE]
Free PMC Article

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