GSE162487
Synthetic lethality by TET-dioxygenase inhibition
To characterize target specificity of TETi76, we performed global gene expression analyses of K562TET2+/+ and TET2-/- control cells; TETi76 mimicked expression signatures generated by the loss of TET2 in K562. The addition of Ascorbic Acid (AA), known to enhance TET-dioxygenase activity, counteracted the changes induced by TETi76. In order to study the molecular pathway of synthetic lethality by TET-dioxygenase inhibition, natural TET2-/- mutant cell line SIGM5 was treated with TET inhibitor TETi76 and global gene expression analysis was performed by RNAseq. Result demostrate a significant upregulation of TNT-a signaling and the down regulation of Interferon-a signaling. Interestingly, we also observed significant up-modulation of oxidative stress response pathway genes consistent with the inhibition of dioxygenases. In particular, TETi76 treatment induces 8-fold increase of oxidative stress sensor NQO1 a NRF2 target gene that has been shown earlier to induce pro-apoptotic cell death in cancer cells. Overall design: SIGM5 and isogenic K562 (TET2+/+ and TET2-/-) cells mRNA profile of TETi76 treatment for 24 hours