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

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 Overall design: To identify the role of proteasome inhibitor (PI)-induced DNMT1/3B downregulation, we knocked down DNMT1 (shDNMT1) and DNMT3B (shDNMT3B) respectively, and performed RNA sequencing to analyze the transcriptome alteration following depleting DNMT1 or DNMT3B