Proteasome inhibition induces alteration of DNA methylation profile by attenuating the synthesis of DNA methyltransferase 1 and 3B in colorectal cancer II

Proteasome is an essential organelle in guarding cellular protein homeostasis. Here, we report that inhibition of proteasome alters the profile of DNA methylation in colorectal cancer (CRC) by blocking the synthesis of DNA methyltransferases (DNMTs). We found that treating CRC cells with proteasome inhibitors (PIs) suppress the translation of DNMT1 and DNMT3B by inactivating AKT and mammalian target of rapamycin (mTOR), dependent on the accumulation of p300, an acetyltransferase inactivating AKT by mediating its acetylation modification. Furthermore, we demonstrated downregulation of DNMT1 and DNMT3B protects cancer cells against PI treatment, potentially by reprogramming the transcriptome of CRC cells; highlighting the key role of DNMTs in response to proteostasis disturbance To evaluate the landscape of DNA methylation in CRC, we treated HT29 cells with MG132 (0.2μM) for 21 passages and using the DMSO-treated cells as control. We used Infinium MethylationEPIC v2.0 BeadChip to profile DNA methylation at passage 14 and 21, respectively.