PARP1 Suppresses the Transcription of PD-L1 by Poly(ADP-Ribosyl)ating STAT3
PARP1 Suppresses the Transcription of PD-L1 by Poly(ADP-Ribosyl)ating STAT3
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PARP1 通过聚 (ADP-核糖基) STAT3 抑制 PD-L1 的转录
DOI：
10.1158/2326-6066.cir-18-0071
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发表时间：
2019-01-01
影响因子：
10.1
通讯作者：
Yang, Bo
中科院分区：
文献类型：
--
作者：
Ding, Ling;Chen, Xi;Yang, Bo
研究表明，PARP1在通过聚（ADP-核糖基）Ating，序列特异性，DNA结合转录因子调节基因表达中的作用。但是，很少有将PARP1作用与癌细胞的免疫原性联系起来的例子。在这里，我们报告了PARP1 poly（ADP-核糖基）ates stat3并随后促进STAT3去磷酸化，从而导致STAT3的转录活性降低和PD-L1的表达。在这项研究中，我们表明PARP1沉默或药理抑制增强了癌细胞中PD-L1的转录，这伴随着PD-L1蛋白表达的上调，无论是在细胞质还是在细胞表面上。在没有转录因子STAT3的情况下，PD-L1的这种诱导被减弱。基于细胞的研究表明，PARP1与STAT3直接相互作用，并导致STAT3聚（ADP-核糖基）。 STAT3通过野生型PARP1的过表达而不是缺乏催化活性的突变体PARP1的过表达来消除STAT3的激活。 PARP1下调或催化抑制增强了STAT3的磷酸化，这是由于野生型PARP1的异位表达而逆转的，但不能突变的PARP1。在临床卵巢癌样品中也观察到PARP1和PD-L1之间的反相关性。总体而言，我们的研究表明，PARP1介导的STAT3的聚（ADP-核糖基）是抑制PD-L1转录的关键步骤，并且这种机制存在于多种癌细胞中。
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.