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

Abstract

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 dephosphorylation, resulting in reduced transcriptional activity of STAT3 and expression of PD-L1. In this study, we showed that PARP1 silencing or pharmacologic 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 overexpression 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.

Multifaceted Role of PARP-1 in DNA Repair and Inflammation: Pathological and Therapeutic Implications in Cancer and Non-Cancer Diseases

“…Of particular interest is the combination of PARPis with the immune checkpoint inhibitors. PARP inhibition promotes differentiation of naïve T cells to Foxp3 + regulatory T cells [104], which suppress immune responses, and upregulates in tumor cells the expression of PD-L1 [139,140], which by engaging PD1 dampens anti-tumor T cell responses favoring tumor immune-evasion. Combined therapy using anti-PD-L1/anti-PD-1 blocking antibodies and PARPis showed synergic effects in mouse models [140] and promising antitumor activity in clinical trials [141].…”

Distinctive roles of syntaxin binding protein 4 and its action target, TP63, in lung squamous cell carcinoma: A theranostic study for the precision medicine

“…Among all the ndings, down-regulation of CD274 caused by TXT and Ramucirumab in RELF-LC-A1 cells was unexpected results, because cellular stress response signals (i.e eIF2, NFkb, mTOR and OXPHOS) modulated by chemotherapeutic drugs are known to mostly up-regulate PD-L1 expression in cancer cells (21)(22)(23). Whereas, we can nd several contradictory ndings that STAT3 silencing, several non-coding RNAs (i.e NKX2-1-AS1 and miR-197), and microtubule targeting agent down-regulates CD274 at transcriptional level (24)(25)(26). It has been also shown that TP63 regulates various miRNAs that affects multiple targets gene transcription (27), and several miRNAs relate to over expression of CD274 (miR-3127-5p, miR135, miR-20b, miR-21, miR-130b) as well as down regulation of CD274 (miRNA142-5p and miR197) (28,29).…”

Transgelin interacts with PARP1 in human colon cancer cells

“…Moreover, Dorsam et al [46] have shown that PARP1 reduced the N-nitroso compounds (NOC)-induced tumorigenesis, regulated intestinal in ammation through innate immune response and promoted colorectal tumor growth. PARP1 has also been suggested to regulate the transcription of genes by directly binding to their promoters [47][48][49]. Taken together, these ndings imply that PARP1 could be a promising target for malignant tumor intervention.…”