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| Status |
Public on Sep 22, 2021 |
| Title |
Targeting DNMTs to overcome enzalutamide resistance in prostate cancer |
| Organism |
Homo sapiens |
| Experiment type |
Expression profiling by high throughput sequencing
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| Summary |
Prostate cancer is the second leading cause of cancer death among men in the United States. The androgen receptor (AR) antagonist enzalutamide is a FDA-approved drug for treatment of patients with late-stage prostate cancer and is currently under clinical study for early-stage prostate cancer treatment. After a short positive response period to enzalutamide, tumors will develop drug resistance. In this study, we uncovered that DNA methylation was deregulated in enzalutamide-resistant cells. DNMT activity and DNMT3B expression were upregulated in resistant cell lines. Enzalutamide induced the expression of DNMT3A and DNMT3B in prostate cancer cells with a potential role of p53 and pRB in this process. The overexpression of DNMT3B3, a DNMT3B variant, promoted an enzalutamide-resistant phenotype in C4-2B cell lines. Inhibition of DNA methylation and DNMT3B knockdown induced a re-sensitization to enzalutamide. Decitabine treatment in enzalutamide-resistant cells induced a decrease of the expression of AR-V7 and changes of genes for apoptosis, DNA repair and mRNA splicing. Combination treatment of Decitabine and enzalutamide induced a decrease of tumor weight, Ki-67 and AR-V7 expression and an increase of cleaved-caspase3 levels in 22Rv1 xenografts. The collective results suggest that DNA methylation pathway is deregulated after enzalutamide resistance onset and that targeting DNA methyltransferases restores the sensitivity to enzalutamide in prostate cancer cells.
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| Overall design |
To study the impact of DNMT3B in enzalutamide resistance, we designed an RNA sequencing experiment depicted in Figure 6A. In this experiment, we compared enzalutamide-sensitive cell lines, LNCaP and C4-2B to the enzalutamide-resistant cell lines, C4-2B-MDVR as comparison 1 (C1) and comparison 2 (C2), respectively. Then we compared untreated C4-2B-MDVR cells to C4-2B-MDVR cells treated with decitabine or decitabine plus enzalutamide as comparison 3 (C3) and comparison 4 (C4), respectively. In these comparisons, we explored the changes of genes expression upon different treatments. This approach allowed us to identify high interest genes and pathways involved in responses to treatments. The expression of these highly interest genes were explored in C3 and C4 to identify any reversal in gene expression compared to C1 and C2. These analyses allowed us to identify a subset of genes that changed in resistantC4-2B-MDVR compared to sensitive cell lines after decitabine treatment.
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| Contributor(s) |
Farah E, Zhang Z, Liu X, Utturkar SM |
| Citation(s) |
34728570 |
| |
| Submission date |
Sep 15, 2021 |
| Last update date |
Dec 22, 2021 |
| Contact name |
Xiaoqi Liu |
| E-mail(s) |
xiaoqi.liu@uky.edu
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| Organization name |
University of Kentucky
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| Department |
Toxicology & Cancer Biology
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| Street address |
760 press Ave
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| City |
Lexington |
| ZIP/Postal code |
40536 |
| Country |
USA |
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| Platforms (1) |
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| Samples (15)
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| Relations |
| BioProject |
PRJNA763500 |
| SRA |
SRP337207 |
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