TY - JOUR
T1 - Epigenetic synergy between decitabine and platinum derivatives
AU - Qin, Taichun
AU - Si, Jiali
AU - Raynal, Noël J.M.
AU - Wang, Xiaodan
AU - Gharibyan, Vazganush
AU - Ahmed, Saira
AU - Hu, Xin
AU - Jin, Chunlei
AU - Lu, Yue
AU - Shu, Jingmin
AU - Estecio, Marcos R.H.
AU - Jelinek, Jaroslav
AU - Issa, Jean Pierre J.
N1 - Funding Information:
This work was supported by the National Institutes of Health grants CA158112 and CA100632 to JPJI. JPJI is an American Cancer Society Clinical Research professor supported by a generous gift from the F.M. Kirby Foundation. Gene expression microarray and high throughput sequencing was supported by Core grant CA016672 (SMF) to The University of Texas MD Anderson Cancer Center.
Publisher Copyright:
© 2015, Qin et al.
PY - 2015/9/11
Y1 - 2015/9/11
N2 - Background: Aberrant epigenetic silencing of tumor suppressor genes has been recognized as a driving force in cancer. Epigenetic drugs such as the DNA methylation inhibitor decitabine reactivate genes and are effective in myeloid leukemia, but resistance often develops and efficacy in solid tumors is limited. To improve their clinical efficacy, we searched among approved anti-cancer drugs for an epigenetic synergistic combination with decitabine. Results: We used the YB5 cell line, a clonal derivative of the SW48 colon cancer cell line that contains a single copy of a hypermethylated cytomegalovirus (CMV) promoter driving green fluorescent protein (GFP) to screen for drug-induced gene reactivation and synergy with decitabine. None of the 16 anti-cancer drugs tested had effects on their own. However, in combination with decitabine, platinum compounds showed striking synergy in activating GFP. This was dose dependent, observed both in concurrent and sequential combinations, and also seen with other alkylating agents. Clinically achievable concentrations of carboplatin at (25 μM) and decitabine reactivated GFP in 28 % of the YB5 cells as compared to 15 % with decitabine alone. Epigenetic synergy was also seen at endogenously hypermethylated tumor suppressor genes such as MLH1 and PDLIM4. Genome-wide studies showed that reactivation of hypermethylated genes by the combination was significantly better than that induced by decitabine alone or carboplatin alone. Platinum compounds did not enhance decitabine-induced hypomethylation. Rather, we found significantly inhibited HP1α expression by carboplatin and the combination. This was accompanied by increased histone H3 lysine 4 (H3K4) trimethylation and histone H3 lysine 9 (H3K9) acetylation at reactivated genes (P < 0.0001) and reduced occupancy by methyl-binding proteins including MeCP2 and methyl-CpG-binding domain protein 2 (MBD2) (P < 0.0001). Conclusions: Our results suggest that the combination of decitabine with platinum analogs shows epigenetic synergy that might be exploited in the treatment of different cancers.
AB - Background: Aberrant epigenetic silencing of tumor suppressor genes has been recognized as a driving force in cancer. Epigenetic drugs such as the DNA methylation inhibitor decitabine reactivate genes and are effective in myeloid leukemia, but resistance often develops and efficacy in solid tumors is limited. To improve their clinical efficacy, we searched among approved anti-cancer drugs for an epigenetic synergistic combination with decitabine. Results: We used the YB5 cell line, a clonal derivative of the SW48 colon cancer cell line that contains a single copy of a hypermethylated cytomegalovirus (CMV) promoter driving green fluorescent protein (GFP) to screen for drug-induced gene reactivation and synergy with decitabine. None of the 16 anti-cancer drugs tested had effects on their own. However, in combination with decitabine, platinum compounds showed striking synergy in activating GFP. This was dose dependent, observed both in concurrent and sequential combinations, and also seen with other alkylating agents. Clinically achievable concentrations of carboplatin at (25 μM) and decitabine reactivated GFP in 28 % of the YB5 cells as compared to 15 % with decitabine alone. Epigenetic synergy was also seen at endogenously hypermethylated tumor suppressor genes such as MLH1 and PDLIM4. Genome-wide studies showed that reactivation of hypermethylated genes by the combination was significantly better than that induced by decitabine alone or carboplatin alone. Platinum compounds did not enhance decitabine-induced hypomethylation. Rather, we found significantly inhibited HP1α expression by carboplatin and the combination. This was accompanied by increased histone H3 lysine 4 (H3K4) trimethylation and histone H3 lysine 9 (H3K9) acetylation at reactivated genes (P < 0.0001) and reduced occupancy by methyl-binding proteins including MeCP2 and methyl-CpG-binding domain protein 2 (MBD2) (P < 0.0001). Conclusions: Our results suggest that the combination of decitabine with platinum analogs shows epigenetic synergy that might be exploited in the treatment of different cancers.
KW - 5-aza-2′-deoxycytidine
KW - Carboplatin
KW - DNA methylation
KW - Epigenetic reactivation
KW - Tumor suppressor genes
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U2 - 10.1186/s13148-015-0131-z
DO - 10.1186/s13148-015-0131-z
M3 - Article
C2 - 26366234
AN - SCOPUS:84941335937
SN - 1868-7075
VL - 7
JO - Clinical epigenetics
JF - Clinical epigenetics
IS - 1
M1 - 97
ER -