Table 4.
Hypomethylation associated with chemotherapy resistance in cancer.
| Cancer type | Hypomethylated promoter | Mechanism associated with hypomethylation and increased expression | Associated resistance |
|---|---|---|---|
| Breast (BC) | ID4 | Potential biomarker in distinguishing acquired tamoxifen-refractory BC | Tamoxifen (161) |
| ERp29/ MGMT | ERp29 expression in the triple negative MDA-MB-231 breast cancer cells significantly increases cell survival against ionizing radiation, by downregulating DNA methyltransferase 1, ERp29 promotes promoter's hypomethylation of the DNA repair gene (MGMT) | Radiation (162) | |
| ETS-1 | Inhibitor of miR-320a expression, downregulation of miR-320a triggers TRPC5 and NFATC3 overexpression, which are essential for BC chemoresistance | Adriamycin and paclitaxel (163) | |
| miR-663 | Overexpression of hypomethylated miR-663 induces chemoresistance in breast cancer cells by down-regulating HSPG2. | Cyclophosphamide and docetaxel (164) | |
| MDR1, GSTpi, MGMT, and Upa | Hypomethylation of the promoter regions of the MDR1, GSTpi, MGMT, and Upa genes is associated with acquirement of doxorubicin resistance of MCF-7 cells | Doxorubicin (165) | |
| Colorectal (CRC) | NME2 | Enhancer of growth abilities and reduced apoptosis in HCT-8 cells | 5-FU (166) |
| CDO1 | CDO1 hypomethylation in stage III colon cancer with postoperative chemotherapy exhibits worst prognosis than CDO1 hypermethylation. In some CRC cell lines, forced expression of CDO1 gene increases mitochondrial membrane potential accompanied by chemoresistance and/or tolerance under hypoxia. | Adjuvant (167) | |
| Nrf2 | TET-dependent demethylation of the Nrf2 promoter upregulates Nrf2 and HO-1 expression, which induces cellular protection mechanisms, leading to 5-FU resistance in CRC cells | 5-FU (168) | |
| Gastric (GC) | ASCL2 | Enhanced ASCL2 expression increases cell growth and promotes resistance to 5-FU in GC cells, a useful prognostic marker for GC patients | 5-FU (169) |
| MDR1 | Overexpression of DCTPP1 decreases the concentration of intracellular 5-methyl-dCTP, which results in promoter hypomethylation and hyper-expression of MDR1 | 5-FU (170) | |
| GTSE1 | GTSE1 expression represses apoptotic signaling and confers cisplatin resistance in gastric cancer cells. | Cisplatin (171) | |
| Hepato-cellular (HCC) | PD-L1/DNMT1 axis | Highly DNMT1 upregulation positively correlates with PD-L1 overexpression in sorafenib-resistant HCC cells, where PD-L1 induced DNMT1-dependent DNA hypomethylation | Sorafenib (172) |
| MDR1 | MDR1 promoter hypomethylation might be regulated by the riboregulatory H19, inducing the P-glycoprotein expression through the upregulation of its gene MDR1 in liver cancer cells | Doxorubicin (173) | |
| Lung (LC) | TDRD9 | Associated with aberrant mitosis and abnormal-shaped nuclei, protects from replicative stress increasing drug resistance | Aphydicolin (174) |
| Ovarian (OC) | SERPINE1 | Associated with EMT process and carboplatin resistance in A2780cp cells | Carboplatin (175) |
| TMEM88 | Functions as an inhibitor of Wnt signaling contributing to the platinum resistance | Platinum (176) | |
| BRCA1/SIRT1/EGFR axis | Cisplatin-resistant ovarian cancers increase BRCA1, SIRT1, and EGFR levels compared with those in cisplatin-sensitive ovarian cancers. Decreased nicotinamide adenine dinucleotide (NAD)-mediated SIRT1 activity, decreased EGFR levels, significantly elevated SIRT1 levels, and BRCA1 activation are associated with hypomethylation in the BRCA1 promoter | Cisplatin (177) | |
| HERV | HERV-K hypomethylation is associated with a poor prognosis and platinum resistance in ovarian clear cell carcinoma (OCCC), promising biomarker for predicting OCCC treatment response and prognosis. | Platinum (178) | |
| MAL | Highly expressed MAL gene in serous ovarian cancers from short-term survivors (<3 years) and treated with platinum-based therapy. MAL methylation status is a potential target for enhancing sensitivity to platinum-based drugs in epithelial ovarian cancer | Platinum (179) | |
| Prostate (PCa) | miR-27a-5p | miR-27a-5p promoter becomes hypomethylated during PCa progression, miR-27a-5p upregulation decreases EGFR/Akt1/mTOR signaling | Castration (180) |
| CD117 and ABCG2 | Prostate cancer cell line 22RV1 expresses high surface levels of both CD117 and ABCG2 (CD117+ABCG2+ cells). This subpopulation shows hypomethylation in ABCG2 promoter and also overexpresses stem cells markers such as Nanog, Oct4, Sox2, Nestin, and CD133 | Cisplatin, paclitaxel, adriamycin, and methotrexate (181) |