PARP1 enhances lung adenocarcinoma metastasis by novel mechanisms independent of DNA repair

• Published in: Oncogene Vol. 35; no. 35; pp. 4569 - 4579
• Main Authors: Choi, E-B, Yang, A-Y, Kim, S C, Lee, J, Choi, J K, Choi, C, Kim, M-Y
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01-09-2016; Nature Publishing Group
• Subjects: 13/1; 13/109; 13/89; 14/5; 38/61; 45/90; 631/154/53/2422; 631/67/1612/1350; 631/67/322; 82/51; Adenocarcinoma; Adenocarcinoma - genetics; Adenocarcinoma - pathology; Adenocarcinoma of Lung; Anoikis; Apoptosis; Cancer; Carcinogenesis; Carcinogenesis - genetics; Cell Biology; Cell Line, Tumor; Claudins - genetics; Clinical trials; Deoxyribonucleic acid; Development and progression; DNA; DNA repair; DNA Repair - genetics; DNA-Binding Proteins - genetics; Extravasation; Gene expression; Gene Expression Regulation, Neoplastic; Gene Knockdown Techniques; Genetic aspects; Health aspects; Homologous Recombination; Human Genetics; Humans; Internal Medicine; Lung cancer; Lung Neoplasms - genetics; Lung Neoplasms - pathology; Medicine; Medicine & Public Health; Metastases; Metastasis; Microenvironments; Molecular modelling; Neoplasm Metastasis; Neoplasm Recurrence, Local - genetics; Neoplasm Recurrence, Local - pathology; Oncology; original-article; Patients; Poly(ADP-ribose) Polymerase 1; Polymerase chain reaction; Properties; Ribose; S100 Calcium-Binding Protein A4 - genetics; S100A4 protein; Transcription; Transferases
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/onc.2016.3

The role of poly (ADP-ribose) polymerase 1 (PARP1) in cancer has been extensively studied in the context of DNA repair, leading to clinical trials of PARP1 inhibitors in cancers defective in homologous recombination. However, the DNA repair-independent roles of PARP1 in carcinogenesis and metastasis, particularly in lung cancer metastasis, remain largely uncharacterized. Here, we report that PARP1 promotes lung adenocarcinoma relapse to the brain and bones by regulating several steps of the metastatic process in a DNA repair-independent manner. We find that
PARP1
expression is associated with overall and distant metastasis-free survival in lung adenocarcinoma patients. Consistent with this, genetic knockdown and pharmacological inhibition of PARP1 significantly attenuated the metastatic potential of lung adenocarcinoma cells. Further investigation revealed that PARP1 potentiates lung adenocarcinoma metastasis by promoting invasion, anoikis resistance, extravasation and self-renewal of lung adenocarcinoma cells and also by modifying the brain microenvironment. Finally, we identified
S100A4
and
CLDN7
as novel transcriptional targets and clinically relevant effectors of PARP1. Collectively, our study not only revealed previously unknown functions of PARP1 in lung adenocarcinoma metastasis but also delineated the molecular mechanisms underlying the pro-metastatic function of PARP1. Furthermore, these findings provide a foundation for the potential use of PARP1 inhibitors as a new treatment option for lung adenocarcinoma patients with elevated
PARP1
expression.