Abstract
FOXM1 transcription factor network is activated in over 84% of cases in high-grade serous ovarian cancer (HGSOC), and FOXM1 upregulates the expression of genes involved in the homologous recombination (HR) DNA damage and repair (DDR) pathway. However, the role of FOXM1 in PARP inhibitor response has not yet been studied. This study demonstrates that PARP inhibitor (PARPi), olaparib, induces the expression and nuclear localization of FOXM1. On the basis of ChIPqPCR, olaparib enhances the binding of FOXM1 to genes involved in HR repair. FOXM1 knockdown by RNAi or inhibition by thiostrepton decreases FOXM1 expression, decreases the expression of HR repair genes, such as BRCA1 and RAD51, and enhances sensitivity to olaparib. Comet and PARP trapping assays revealed increases in DNA damage and PARP trapping in FOXM1-inhibited cells treated with olaparib. Finally, thiostrepton decreases the expression of BRCA1 in rucaparib-resistant cells and enhances sensitivity to rucaparib. Collectively, these results identify that FOXM1 plays an important role in the adaptive response induced by olaparib and FOXM1 inhibition by thiostrepton induces "BRCAness" and enhances sensitivity to PARP inhibitors. Implications: FOXM1 inhibition represents an effective strategy to overcome resistance to PARPi, and targeting FOXM1-mediated adaptive pathways may produce better therapeutic effects for PARP inhibitors. Mol Cancer Res; 16(6); 961-73.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 961-973 |
| Number of pages | 13 |
| Journal | Molecular Cancer Research |
| Volume | 16 |
| Issue number | 6 |
| DOIs | |
| State | Published - Jun 1 2018 |
| Externally published | Yes |
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ASJC Scopus subject areas
- Molecular Biology
- Oncology
- Cancer Research
Cite this
Olaparib-induced adaptive response Is disrupted by FOXM1 targeting that enhances sensitivity to PARP inhibition. / Fang, Pingping; Madden, Jill A.; Neums, Lisa; Moulder, Ryan K.; Forrest, M. Laird; Chien, Jeremy.
In: Molecular Cancer Research, Vol. 16, No. 6, 01.06.2018, p. 961-973.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Olaparib-induced adaptive response Is disrupted by FOXM1 targeting that enhances sensitivity to PARP inhibition
AU - Fang, Pingping
AU - Madden, Jill A.
AU - Neums, Lisa
AU - Moulder, Ryan K.
AU - Forrest, M. Laird
AU - Chien, Jeremy
PY - 2018/6/1
Y1 - 2018/6/1
N2 - FOXM1 transcription factor network is activated in over 84% of cases in high-grade serous ovarian cancer (HGSOC), and FOXM1 upregulates the expression of genes involved in the homologous recombination (HR) DNA damage and repair (DDR) pathway. However, the role of FOXM1 in PARP inhibitor response has not yet been studied. This study demonstrates that PARP inhibitor (PARPi), olaparib, induces the expression and nuclear localization of FOXM1. On the basis of ChIPqPCR, olaparib enhances the binding of FOXM1 to genes involved in HR repair. FOXM1 knockdown by RNAi or inhibition by thiostrepton decreases FOXM1 expression, decreases the expression of HR repair genes, such as BRCA1 and RAD51, and enhances sensitivity to olaparib. Comet and PARP trapping assays revealed increases in DNA damage and PARP trapping in FOXM1-inhibited cells treated with olaparib. Finally, thiostrepton decreases the expression of BRCA1 in rucaparib-resistant cells and enhances sensitivity to rucaparib. Collectively, these results identify that FOXM1 plays an important role in the adaptive response induced by olaparib and FOXM1 inhibition by thiostrepton induces "BRCAness" and enhances sensitivity to PARP inhibitors. Implications: FOXM1 inhibition represents an effective strategy to overcome resistance to PARPi, and targeting FOXM1-mediated adaptive pathways may produce better therapeutic effects for PARP inhibitors. Mol Cancer Res; 16(6); 961-73.
AB - FOXM1 transcription factor network is activated in over 84% of cases in high-grade serous ovarian cancer (HGSOC), and FOXM1 upregulates the expression of genes involved in the homologous recombination (HR) DNA damage and repair (DDR) pathway. However, the role of FOXM1 in PARP inhibitor response has not yet been studied. This study demonstrates that PARP inhibitor (PARPi), olaparib, induces the expression and nuclear localization of FOXM1. On the basis of ChIPqPCR, olaparib enhances the binding of FOXM1 to genes involved in HR repair. FOXM1 knockdown by RNAi or inhibition by thiostrepton decreases FOXM1 expression, decreases the expression of HR repair genes, such as BRCA1 and RAD51, and enhances sensitivity to olaparib. Comet and PARP trapping assays revealed increases in DNA damage and PARP trapping in FOXM1-inhibited cells treated with olaparib. Finally, thiostrepton decreases the expression of BRCA1 in rucaparib-resistant cells and enhances sensitivity to rucaparib. Collectively, these results identify that FOXM1 plays an important role in the adaptive response induced by olaparib and FOXM1 inhibition by thiostrepton induces "BRCAness" and enhances sensitivity to PARP inhibitors. Implications: FOXM1 inhibition represents an effective strategy to overcome resistance to PARPi, and targeting FOXM1-mediated adaptive pathways may produce better therapeutic effects for PARP inhibitors. Mol Cancer Res; 16(6); 961-73.
UR - http://www.scopus.com/inward/record.url?scp=85048234059&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85048234059&partnerID=8YFLogxK
U2 - 10.1158/1541-7786.MCR-17-0607
DO - 10.1158/1541-7786.MCR-17-0607
M3 - Article
C2 - 29545475
AN - SCOPUS:85048234059
VL - 16
SP - 961
EP - 973
JO - Molecular Cancer Research
JF - Molecular Cancer Research
SN - 1541-7786
IS - 6
ER -