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

Abstract

Dysregulation of PARP10 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 PARP10 in HCC remain mostly unknown. The crosstalk between PLK1, PARP10, 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 PARP10 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 PARP10 at T601. PARP10 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 PARP10 promoter activity and leads to its downregulation in HCC. Interestingly, PLK1 is mono-ADP-ribosylated by PARP10 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 PARP10 expression in human HCC tissues. These findings are the first to uncover a PLK1/PARP10/NF-κB signaling circuit that underlies tumorigenesis and validate PLK1 inhibitors, alone or with NF-κB antagonists, as potential effective therapeutics for PARP10-expressing HCC.

• Authors: Lantian Tian, Ke Yao, Kun Liu, Bing Han, Hanguang Dong, Wei Zhao, Weibo Jiang, Fabo Qiu, Linlin Qu, Zehua Wu, Bin Zhou, Mengya Zhong, Jiabao Zhao, Xingfeng Qiu, Lifeng Zhong, Xiaofeng Guo, Tianlu Shi, Xuehui Hong, Shichun Lu
• Journal: Oncogene (Oncogene) Vol. 39 Issue 15 Pg. 3145-3162 (04 2020) ISSN: 1476-5594 [Electronic] England
• PMID: 32060423 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• 3-(4-methylphenylsulfonyl)-2-propenenitrile
• Antineoplastic Agents
• BI 2536
• Cell Cycle Proteins
• Nitriles
• Proto-Oncogene Proteins
• Pteridines
• RELA protein, human
• Sulfones
• Transcription Factor RelA
• PARP10 protein, human
• Poly(ADP-ribose) Polymerases
• Protein Serine-Threonine Kinases
• polo-like kinase 1
• Staurosporine

Topics

• Animals
• Antineoplastic Agents (pharmacology, therapeutic use)
• Carcinogenesis (drug effects, pathology)
• Carcinoma, Hepatocellular (mortality, pathology, therapy)
• Cell Cycle Proteins (antagonists & inhibitors, metabolism)
• Disease Progression
• Feedback, Physiological
• Female
• HEK293 Cells
• Hepatectomy
• Humans
• Kaplan-Meier Estimate
• Liver (pathology, surgery)
• Liver Neoplasms (mortality, pathology, therapy)
• Male
• Mice
• Middle Aged
• Mutagenesis, Site-Directed
• Neoplasm Staging
• Nitriles (pharmacology, therapeutic use)
• Phosphorylation (drug effects)
• Poly(ADP-ribose) Polymerases (genetics, metabolism)
• Protein Serine-Threonine Kinases (antagonists & inhibitors, metabolism)
• Proto-Oncogene Proteins (antagonists & inhibitors, genetics, metabolism)
• Pteridines (pharmacology, therapeutic use)
• Signal Transduction (drug effects, genetics)
• Staurosporine (pharmacology, therapeutic use)
• Sulfones (pharmacology, therapeutic use)
• Transcription Factor RelA (antagonists & inhibitors, metabolism)
• Xenograft Model Antitumor Assays