Targeting Translational Control in Cancer Using Small Molecule Activators of PP2A.

SMAPs promote PP2A-dependent proteasomal degradation of Snail/Slug protein via a non-canonical mechanism, as well as upregulation of ATF4. We propose that these effects relieve transcriptional repression of 4E-BP1 by Snail/Slug while promoting 4E-BP1 transcription by ATF4, leading to a robust increase in 4E-BP1 levels. 4E-BP1 translation repressive activity is ensured by PP2A-induced 4E-BP1 dephosphorylation. Thus, SMAPs offer a powerful tool for therapeutic targeting of aberrant protein translation in cancer.