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Cancer Immunol Res. 2018 Nov 6. pii: canimm.0071.2018. doi: 10.1158/2326-6066.CIR-18-0071. [Epub ahead of print]

PARP1 Suppresses the Transcription of PD-L1 by Poly(ADP-Ribosyl)ating STAT3.

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College of Pharmaceutical Sciences, Zhejiang University.
Zhejiang University.
Department of Reproductive Endocrinology, Women's Hospital, School of Medicine, Zhejiang University.
College of Pharmaceutical Sciences, Pharmacology and Toxicology.
Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University.
College of Pharmaceutical Sciences, Zhejiang University


Studies have pointed to a role of PARP1 in regulating gene expression through poly(ADP-ribosyl)ating, sequence-specific, DNA-binding transcription factors. However, few examples exist that link this role of PARP1 to the immunogenicity of cancer cells. Here, we report that PARP1 poly(ADP-ribosyl)ates STAT3 and subsequently promotes STAT3 de-phosphorylation, resulting in reduced transcriptional activity of STAT3 and expression of PD-L1. In this study, we showed that PARP1 silencing or pharmacological inhibition enhanced the transcription of PD-L1 in cancer cells, which was accompanied by the upregulation of PD-L1 protein expression, both in the cytoplasm and on the cell surface. This induction of PD-L1 was attenuated in the absence of the transcription factor STAT3. Cell-based studies indicated that PARP1 interacted directly with STAT3 and caused STAT3 poly(ADP-ribosyl)ation. STAT3's activation of PD-L1 transcription was abolished by the over-expression of wild-type PARP1 but not mutant PARP1, which lacks catalytic activity. PARP1 downregulation or catalytic inhibition enhanced the phosphorylation of STAT3, which was reversed by the ectopic expression of wild-type PARP1 but not by mutated PARP1. An inverse correlation between PARP1 and PD-L1 was also observed in clinical ovarian cancer samples. Overall, our study revealed PARP1-mediated poly(ADP-ribosyl)ation of STAT3 as a key step in inhibiting the transcription of PD-L1, and this mechanism exists in a variety of cancer cells.

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