TY - JOUR
T1 - Hedgehog/GLI1 Transcriptionally Regulates FANCD2 in Ovarian Tumor Cells
T2 - Its Inhibition Induces HR-Deficiency and Synergistic Lethality with PARP Inhibition.
AU - Mani, Chinnadurai
AU - Tripathi, Kaushlendra
AU - Chaudhary, Sandeep
AU - Somasagara, Ranganatha R.
AU - Rocconi, Rodney P.
AU - Crasto, Chiquito
AU - Reedy, Mark
AU - Athar, Mohammad
AU - Palle, Komaraiah
N1 - Funding Information:
Ovarian cancer (OC), Hedgehog (Hh), Glioma associated protein 1 (GLI1), Fanconi anemia (FA), Poly (ADP-ribose) polymerase inhibitors (PARPi), Homologous recombination (HR), DNA damage response (DDR), Human epidermal growth factor (EGF), Fibroblast growth factor (FGF), This work was supported by National Cancer Institute (R01CA219187). C.M. K.T. and K.P. Conceptualization, Data curation; C.M. K.T. S.C. R.S. and K.P. Investigation, Methodology. C.M. K.T. S.C. R.S. R.P. M.R. M.A. and K.P. analyzed the data. C.M. K.T. S.C. R.S. R.P. M.R. M.A. and K.P. Visualization, Writing. C.M. K.T. S.C. R.S. R.P. M.R. M.A. and K.P. Investigation, Validation. C.C. Software. M.A and K.P. Resources, Supervision. All animal experiments have been approved by the Institutional review board at University of Alabama at Birmingham, USA. All authors have agreed to publish this manuscript. The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. We thank Palle lab members for their help towards submission of the manuscript. All data that support the findings of this study are available from the corresponding authors upon reasonable request.
Funding Information:
This work was supported by National Cancer Institute (R01CA219187).
Publisher Copyright:
© 2021 The Authors
PY - 2021/9
Y1 - 2021/9
N2 - Ovarian cancer (OC) is one of the most lethal type of cancer in women due to a lack of effective targeted therapies and high rates of treatment resistance and disease recurrence. Recently Poly (ADP-ribose) polymerase inhibitors (PARPi) have shown promise as chemotherapeutic agents; however, their efficacy is limited to a small fraction of patients with BRCA mutations. Here we show a novel function for the Hedgehog (Hh) transcription factor Glioma associated protein 1 (GLI1) in regulation of key Fanconi anemia (FA) gene, FANCD2 in OC cells. GLI1 inhibition in HR-proficient OC cells induces HR deficiency (BRCAness), replication stress and synergistic lethality when combined with PARP inhibition. Treatment of OC cells with combination of GLI1 and PARP inhibitors shows enhanced DNA damage, synergy in cytotoxicity, and strong in vivo anticancer responses.
AB - Ovarian cancer (OC) is one of the most lethal type of cancer in women due to a lack of effective targeted therapies and high rates of treatment resistance and disease recurrence. Recently Poly (ADP-ribose) polymerase inhibitors (PARPi) have shown promise as chemotherapeutic agents; however, their efficacy is limited to a small fraction of patients with BRCA mutations. Here we show a novel function for the Hedgehog (Hh) transcription factor Glioma associated protein 1 (GLI1) in regulation of key Fanconi anemia (FA) gene, FANCD2 in OC cells. GLI1 inhibition in HR-proficient OC cells induces HR deficiency (BRCAness), replication stress and synergistic lethality when combined with PARP inhibition. Treatment of OC cells with combination of GLI1 and PARP inhibitors shows enhanced DNA damage, synergy in cytotoxicity, and strong in vivo anticancer responses.
KW - FANCD2
KW - GANT61
KW - GLI1
KW - Homologous recombination deficiency
KW - Olaparib
KW - Ovarian Cancer
UR - http://www.scopus.com/inward/record.url?scp=85111953721&partnerID=8YFLogxK
U2 - 10.1016/j.neo.2021.06.010
DO - 10.1016/j.neo.2021.06.010
M3 - Article
C2 - 34380074
AN - SCOPUS:85111953721
VL - 23
SP - 1002
EP - 1015
JO - Neoplasia (United States)
JF - Neoplasia (United States)
SN - 1522-8002
IS - 9
ER -