title: PARP1 enhances lung adenocarcinoma metastasis by novel mechanisms independent of DNA repair.
abstract: 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.
authors.affiliation: Department of Biological Sciences, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, Republic of Korea.
authors.forename: E-B
authors.initials: EB
authors.lastname: Choi
authors.affiliation: Department of Biological Sciences, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, Republic of Korea.
authors.forename: A-Y
authors.initials: AY
authors.lastname: Yang
authors.affiliation: Department of Biomedical Informatics, Center for Genome Science, National Institute of Health, KCDC, Choongchung-Buk-do, Republic of Korea.
authors.forename: S C
authors.initials: SC
authors.lastname: Kim
authors.affiliation: Department of Bio and Brain Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, Republic of Korea.
authors.forename: J
authors.initials: J
authors.lastname: Lee
authors.affiliation: Department of Bio and Brain Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, Republic of Korea.
authors.forename: J K
authors.initials: JK
authors.lastname: Choi
authors.affiliation: Department of Bio and Brain Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, Republic of Korea.|KAIST Institute for the BioCentury, Cancer Metastasis Control Center, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, Republic of Korea.
authors.forename: C
authors.initials: C
authors.lastname: Choi
authors.affiliation: Department of Biological Sciences, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, Republic of Korea.|KAIST Institute for the BioCentury, Cancer Metastasis Control Center, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, Republic of Korea.
authors.forename: M-Y
authors.initials: MY
authors.lastname: Kim
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics* / Q000473:pathology; D000077192:Adenocarcinoma of Lung; D063646:Carcinogenesis / Q000235:genetics; D045744:Cell Line, Tumor; D057167:Claudins / Q000235:genetics*; D004260:DNA Repair / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic; D055785:Gene Knockdown Techniques; D059765:Homologous Recombination; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics* / Q000473:pathology; D009362:Neoplasm Metastasis; D009364:Neoplasm Recurrence, Local / Q000235:genetics* / Q000473:pathology; D000071999:S100 Calcium-Binding Protein A4 / Q000235:genetics
chemical_list: C473255:CLDN7 protein, human; D057167:Claudins; D004268:DNA-Binding Proteins; C556015:PARPBP protein, human; D000071999:S100 Calcium-Binding Protein A4; C077591:S100A4 protein, human