The Catalytic Subunit of Protein Phosphatase 2A (PP2Ac) Promotes DNA Hypomethylation by Suppressing the Phosphorylated Mitogen-activated Protein Kinase/Extracellular Signal-regulated Kinase (ERK) Kinase (MEK)/Phosphorylated ERK/DNMT1 Protein Pathway in T-cells from Controls and Systemic Lupus Erythematosus Patients

DNA hypomethylation is a characteristic feature of systemic lupus erythematosus (SLE) immune cells. Numerous reports have implicated the involvement of the MEK/ERK pathway in the reduction of DNA methyltransferase (DNMT) expression, hence inducing the transcription of methylation-sensitive genes in SLE patients. However, the molecular mechanisms involved remain unclear. Here, we investigated whether the catalytic subunit of protein phosphatase 2A (PP2Ac), which is overexpressed in SLE T-cells, contributes to reduced DNA methylation. We show that both chemical suppression and siRNA silencing of PP2Ac in T-cells resulted in sustained phosphorylation of MEK and ERK following stimulation with phorbol 12-myristate 13-acetate and ionomycin. Furthermore, PP2Ac suppression resulted in increased DNMT enzyme activity, DNA hypermethylation, and decreased expression of methylation-sensitive genes. Similarly, in SLE T-cells, suppression of PP2Ac resulted in increased MEK/ERK phosphorylation, enhanced DNMT1 expression and suppressed expression of the methylation-sensitive CD70 gene. Our results demonstrate that PP2A regulates DNA methylation by influencing the phosphorylation of MEK/ERK. We propose that enhanced PP2Ac in SLE T-cells may dephosphorylate and activate the signaling pathway upstream of DNMT1, thus disturbing the tight control of methylation-sensitive genes, which are involved in SLE pathogenesis. Background: PP2A is a serine/threonine phosphatase with a central role in the pathogenesis of SLE. Results: Suppression of PP2A mediates increased DNA methylation through the MEK/ERK/DNMT1 pathway in normal and SLE T-cells. Conclusion: PP2A overexpression accounts for DNA hypomethylation in SLE T-cells. Significance: Here, we propose a link between increased PP2A expression and reduced DNA methylation in SLE.