DNMT2/TRDMT1 gene knockout compromises doxorubicin-induced unfolded protein response and sensitizes cancer cells to ER stress-induced apoptosis

Abstract

The acidic, hypoxic and nutrient-deprived tumor microenvironment may induce endoplasmic reticulum (ER) stress and the unfolded protein response (UPR) may exert an important cytoprotective role by promoting folding of newly synthesized proteins and cancer cell survival. The lack of DNMT2/TRDMT1 methyltransferase-mediated C38 tRNA methylation compromises translational fidelity that may result in the accumulation of misfolded and aggregated proteins leading to proteotoxic stress-related cell death. In the present study, DNMT2/TRDMT1 gene knockout-mediated effects were investigated during doxorubicin (DOX)-induced ER stress and PERK-, IRE1- and ATF6-orchestrated UPR in four genetically different cellular models of cancer (breast and cervical cancer, osteosarcoma and glioblastoma cells). Upon DOX stimulation, DNMT2/TRDMT1 gene knockout impaired PERK activation and modulated NSUN and 5-methylcytosine RNA-based responses and microRNA profiles. The lack of DNMT2/TRDMT1 gene in DOX-treated four cancer cell lines resulted in decreased levels of four microRNAs, namely, miR-23a-3p, miR-93-5p, miR-125a-5p and miR-191-5p involved in the regulation of several pathways such as ubiquitin-mediated proteolysis, amino acid degradation and translational misregulation in cancer. We conclude that DNMT2/TRDMT1 gene knockout, at least in selected cellular cancer models, affects adaptive responses associated with protein homeostasis networks that during prolonged ER stress may result in increased sensitivity to apoptotic cell death.

Autophagy degrades immunogenic endogenous retroelements induced by 5-azacytidine in acute myeloid leukemia

“…Finally, siRNA knock-down of DNMT2 increased protein aggregation levels, in agreement with previous studies (Fig. S 7B ) [ 47 ]. Altogether, these results show that the immunopeptidome of AZA-treated cells is significantly impacted by the DNMT2 inhibition mediated by AZA.…”

Knockout of TRDMT1 methyltransferase affects DNA methylome in glioblastoma cells

“…TRDMT1 KO also affected the levels of 5-methylcytosine RNA methyltransferase NSUN family in chemotherapy-stimulated senescent glioblastoma cells [ 14 ]. Furthermore, TRDMT1 KO modulated microRNA pools during doxorubicin-induced ER stress in glioblastoma cells [ 15 ]. Thus, TRDMT1 may regulate gene expression by different mechanisms in glioblastoma cells.…”

“…In conclusion, we have shown that apart from TRDMT1-mediated regulation of gene expression by RNA modification [ 20 ], microRNA [ 15 ] and lcnRNA [ 23 ], TRDMT1 may be also a modulator of DNA methylation-based epigenetic control of gene expression. However, more studies are needed to reveal a molecular mechanism of TRDMT1-associated modulation of DNA methylome and its consequences in cancer cells.…”

“…More recently, we have shown that TRDMT1 KO may modulate chemotherapy-associated responses that affected genetic stability and promoted cellular heterogeneity in stress-induced senescent glioblastoma cells [ 14 ]. TRDMT1 KO also affected microRNA pools during doxorubicin-stimulated ER stress in glioblastoma cells [ 15 ]. However, there are no data on TRDMT1-mediated changes in DNA methylome and related signaling pathways in cancer cells.…”

Research progress on the beneficial effects of exercise on endocrine system-related diseases in women by regulating ER stress pathways

“…The above study illustrates that the expression level of ER stress related proteins is associated with the occurrence and development of cervical cancer. ER stress activation might have a high value in the treatment and prognosis of cervical cancer and has good clinical prospects [71,72].…”