Using a combination of A172 human glioblastoma cells, ApoE<sup>3/4</sup> and ApoE<sup>-/-</sup> NSC and human postmortem tissue, we now demonstrate that ApoE not only binds to the PPP2R5E promoter but also triggers a significant reduction in PP2A activity by two mechanisms: 1) ApoE transcriptionally represses PPP2R5E and reduces protein expression, and 2) ApoE triggers demethylation of the catalytic subunit (PP2A<sub>C</sub>) of PP2A, resulting in the disruption of the PPP2R5E-PP2A<sub>C</sub> complex.
We validated this result by demonstrating that the exogenous addition of DRMs to glioblastoma cells in vitro results in oncogene activation as well as the simultaneous downregulation of Ser/Thr phosphatase PP2A.