Regulation of a PRMT5/NF-κB Axis by Phosphorylation of PRMT5 at Serine 15 in Colorectal Cancer
dc.contributor.author | Hartley, Antja-Voy | |
dc.contributor.author | Wang, Benlian | |
dc.contributor.author | Jiang, Guanglong | |
dc.contributor.author | Wei, Han | |
dc.contributor.author | Sun, Mengyao | |
dc.contributor.author | Prabhu, Lakshmi | |
dc.contributor.author | Martin, Matthew | |
dc.contributor.author | Safa, Ahmad | |
dc.contributor.author | Sun, Steven | |
dc.contributor.author | Liu, Yunlong | |
dc.contributor.author | Lu, Tao | |
dc.contributor.department | Pharmacology and Toxicology, School of Medicine | en_US |
dc.date.accessioned | 2020-11-09T19:21:03Z | |
dc.date.available | 2020-11-09T19:21:03Z | |
dc.date.issued | 2020-05-23 | |
dc.description.abstract | patients. Importantly, our previous work demonstrated that PRMT5 overexpression could substantially augment activation of the nuclear factor kappa B (NF-κB) via methylation of arginine 30 (R30) on its p65 subunit, while knockdown of PRMT5 showed the opposite effect. However, the precise mechanisms governing this PRMT5/NF-κB axis are still largely unknown. Here, we report a novel finding that PRMT5 is phosphorylated on serine 15 (S15) in response to interleukin-1β (IL-1β) stimulation. Interestingly, we identified for the first time that the oncogenic kinase, PKCι could catalyze this phosphorylation event. Overexpression of the serine-to-alanine mutant of PRMT5 (S15A), in either HEK293 cells or CRC cells HT29, DLD1, and HCT116 attenuated NF-κB transactivation compared to WT-PRMT5, confirming that S15 phosphorylation is critical for the activation of NF-κB by PRMT5. Furthermore, the S15A mutant when compared to WT-PRMT5, could downregulate a subset of IL-1β-inducible NF-κB-target genes which correlated with attenuated promoter occupancy of p65 at its target genes. Additionally, the S15A mutant reduced IL-1β-induced methyltransferase activity of PRMT5 and disrupted the interaction of PRMT5 with p65. Furthermore, our data indicate that blockade of PKCι-regulated PRMT5-mediated activation of NF-κB was likely through phosphorylation of PRMT5 at S15. Finally, inhibition of PKCι or overexpression of the S15A mutant attenuated the growth, migratory, and colony-forming abilities of CRC cells compared to the WT-PRMT5. Collectively, we have identified a novel PKCι/PRMT5/NF-κB signaling axis, suggesting that pharmacological disruption of this pivotal axis could serve as the basis for new anti-cancer therapeutics. | en_US |
dc.identifier.citation | Hartley, A.-V., Wang, B., Jiang, G., Wei, H., Sun, M., Prabhu, L., Martin, M., Safa, A., Sun, S., Liu, Y., & Lu, T. (2020). Regulation of a PRMT5/NF-κB Axis by Phosphorylation of PRMT5 at Serine 15 in Colorectal Cancer. International Journal of Molecular Sciences, 21(10), 3684. https://doi.org/10.3390/ijms21103684 | en_US |
dc.identifier.uri | https://hdl.handle.net/1805/24346 | |
dc.language.iso | en_US | en_US |
dc.publisher | MDPI | en_US |
dc.relation.isversionof | 10.3390/ijms21103684 | en_US |
dc.relation.journal | International Journal of Molecular Sciences | en_US |
dc.rights | Attribution 4.0 International | * |
dc.rights.uri | http://creativecommons.org/licenses/by/4.0/ | * |
dc.source | PMC | en_US |
dc.subject | colorectal cancer | en_US |
dc.subject | NF-κB | en_US |
dc.subject | phosphorylation | en_US |
dc.subject | PRMT5 | en_US |
dc.subject | serine | en_US |
dc.title | Regulation of a PRMT5/NF-κB Axis by Phosphorylation of PRMT5 at Serine 15 in Colorectal Cancer | en_US |
dc.type | Article | en_US |