Regulation of a PRMT5/NF-κB Axis by Phosphorylation of PRMT5 at Serine 15 in Colorectal Cancer

dc.contributor.authorHartley, Antja-Voy
dc.contributor.authorWang, Benlian
dc.contributor.authorJiang, Guanglong
dc.contributor.authorWei, Han
dc.contributor.authorSun, Mengyao
dc.contributor.authorPrabhu, Lakshmi
dc.contributor.authorMartin, Matthew
dc.contributor.authorSafa, Ahmad
dc.contributor.authorSun, Steven
dc.contributor.authorLiu, Yunlong
dc.contributor.authorLu, Tao
dc.contributor.departmentPharmacology and Toxicology, School of Medicineen_US
dc.date.accessioned2020-11-09T19:21:03Z
dc.date.available2020-11-09T19:21:03Z
dc.date.issued2020-05-23
dc.description.abstractpatients. 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.citationHartley, 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/ijms21103684en_US
dc.identifier.urihttps://hdl.handle.net/1805/24346
dc.language.isoen_USen_US
dc.publisherMDPIen_US
dc.relation.isversionof10.3390/ijms21103684en_US
dc.relation.journalInternational Journal of Molecular Sciencesen_US
dc.rightsAttribution 4.0 International*
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/*
dc.sourcePMCen_US
dc.subjectcolorectal canceren_US
dc.subjectNF-κBen_US
dc.subjectphosphorylationen_US
dc.subjectPRMT5en_US
dc.subjectserineen_US
dc.titleRegulation of a PRMT5/NF-κB Axis by Phosphorylation of PRMT5 at Serine 15 in Colorectal Canceren_US
dc.typeArticleen_US
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