PLK1/NF-κB feedforward circuit antagonizes the mono-ADP-ribosyltransferase activity of PARP10 and facilitates HCC progression.

Dysregulation of has been implicated in various tumor types and plays a vital role in delaying hepatocellular carcinoma (HCC) progression. However, the mechanisms controlling the expression and activity of Pduanyu3710 in HCC remain mostly unknown. The crosstalk between PLK1, and NF-κB pathway in HCC was determined by performing different in vitro and in vivo assays, including mass spectrometry, kinase, MARylation, chromatin immunoprecipitation, and luciferase reporter measurements. Functional examination was performed by using small chemical drug, cell culture, and mice HCC models. Correlation between PLK1, NF-κB, and Pduanyu3710 expression was determined by analyzing clinical samples of HCC patients with using immunohistochemistry. PLK1, an important regulator for cell mitosis, directly interacts with and phosphorylates Pduanyu3710 at T601. Pduanyu3710 phosphorylation at T601 significantly decreases its binding to NEMO and disrupts its inhibition to NEMO ubiquitination, thereby enhancing the transcription activity of NF-κB toward multiple target genes and promoting HCC development. In turn, NF-κB transcriptionally inhibits the Pduanyu3710 promoter activity and leads to its downregulation in HCC. Interestingly, PLK1 is mono-ADP-ribosylated by Pduanyu3710 and the MARylation of PLK1 significantly inhibits its kinase activity and oncogenic function in HCC. Clinically, the expression levels of PLK1 and phosphor-p65 show an inverse correlation with Pduanyu3710 expression in human HCC tissues. These findings are the first to uncover a signaling circuit that underlies tumorigenesis and validate PLK1 inhibitors, alone or with NF-κB antagonists, as potential effective therapeutics for HCC.

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