PARP10 suppresses tumor metastasis through regulation of Aurora A activity

Abstract

ADP-ribosylation, including poly-ADP-ribosylation (PARylation) and mono-ADP-ribosylation (MARylation), is a multifunctional post-translational modification catalyzed by intracellular ADP-ribosyltransferases (ARTDs or PARPs). Although PARylation has been investigated most thoroughly, the function of MARylation is currently largely undefined. Here, we provide evidences that deficiency of PARP10, a mono-ADP-ribosyltransferase, markedly increased the migration and invasion of tumor cells through regulation of epithelial-mesenchymal transition (EMT), and PARP10 inhibited tumor metastasis in vivo, which was dependent on its enzyme activity. Mechanistically, we found that PARP10 interacted with and mono-ADP-ribosylated Aurora A, and inhibited its kinase activity, thereby regulating its downstream signaling. Moreover, the expression level of PARP10 was downregulated in intrahepatic metastatic hepatocellular carcinoma (HCC) compared with its corresponding primary HCC and adjacent non-tumorous tissues. Taken together, our results indicated that PARP10 has an important role in tumor metastasis suppression via negatively regulation of Aurora A activity.

PARP10 promotes cellular proliferation and tumorigenesis by alleviating replication stress

“…While we cannot exclude an impact of this process on the tumor-promoting activity of PARP10, our data clearly show that PARP10 enhances replication fork elongation at the molecular level, thus strongly arguing that replication stress suppression through TLS engagement is a major component of the oncogenic activity of PARP10. Another recent paper described a role for PARP10 in cell motility through regulating Aurora A activity (13). Interestingly, the authors also created PARP10-knockout HeLa cells and found increased cell motility in vitro, and increased metastasis in vivo (using an experimental approach in which they injected the HeLa cells in the tail vein of Balb/C mice and measured lung metastases).…”

“…Subsequently it has been proposed to be important for the G1/S cell cycle transition (9) as well as for caspase-dependent apoptosis (10). More recently, it was shown that PARP10 can suppress cytokineinduced activation of the NFκB pathway (11), and plays roles in mitochondrial oxidation (12) and cell migration (13).…”

RNF114 suppresses tumour metastasis through the regulation of PARP10

“…Recently, we identi ed Aurora A as a functional partner of PARP10 through tandem a nity puri cation [13]. In addition to Aurora A, RNF114, a ubiquitin E3 ligase [22], was found in the PARP10 complex, suggesting that RNF114 might also be a PARP10-interacting protein.…”

“…transcriptional regulation [7,8], the unfolded protein response [9], DNA repair [10], insulin secretion [11], immunity [12] and tumour development [13]. While much is known about the cellular roles of PARPs that catalyse PARylation, the function of the PARPs that catalyse MARylation is substantially less understood.…”

“…We found that the expression level of PARP10 was lower in intrahepatic metastatic hepatocellular carcinoma (HCC) compared with its level in corresponding primary HCC and adjacent non-tumour tissues. We demonstrated that, mechanistically, PARP10 interacts with mono-ADP-ribosylated Aurora A and inhibits its kinase activity, thereby regulating Aurora A downstream signalling to suppress tumour cell epithelialmesenchymal transition (EMT) processes and tumour metastasis [13].…”