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

ABSTRACT: The overexpression of PRMT5 is highly correlated to poor clinical outcomes for colorectal cancer (CRC) patients. Importantly, our previous work demonstrated that PRMT5 overexpression could substantially augment activation of the nuclear factor kappa B (NF-?B) 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-?B axis are still largely unknown. Here, we report a novel finding that PRMT5 is phosphorylated on serine 15 (S15) in response to interleukin-1? (IL-1?) stimulation. Interestingly, we identified for the first time that the oncogenic kinase, PKC? 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-?B transactivation compared to WT-PRMT5, confirming that S15 phosphorylation is critical for the activation of NF-?B by PRMT5. Furthermore, the S15A mutant when compared to WT-PRMT5, could downregulate a subset of IL-1?-inducible NF-?B-target genes which correlated with attenuated promoter occupancy of p65 at its target genes. Additionally, the S15A mutant reduced IL-1?-induced methyltransferase activity of PRMT5 and disrupted the interaction of PRMT5 with p65. Furthermore, our data indicate that blockade of PKC?-regulated PRMT5-mediated activation of NF-?B was likely through phosphorylation of PRMT5 at S15. Finally, inhibition of PKC? 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 PKC?/PRMT5/NF-?B signaling axis, suggesting that pharmacological disruption of this pivotal axis could serve as the basis for new anti-cancer therapeutics.

SUBMITTER: Hartley AV 

PROVIDER: S-EPMC7279388 | biostudies-literature | 2020 May

REPOSITORIES: biostudies-literature