Abstract
The FOXM1 transcription factor is an oncoprotein and a top biomarker of poor prognosis in human cancer. Overexpression and activation of FOXM1 is frequent in high-grade serous carcinoma (HGSC), the most common and lethal form of human ovarian cancer, and is linked to copy number gains at chromosome 12p13.33. We show that FOXM1 is co-amplified and co-expressed with RHNO1, a gene involved in the ATR-Chk1 signaling pathway that functions in the DNA replication stress response. We demonstrate that FOXM1 and RHNO1 are head-to-head (i.e., bidirectional) genes (BDG) regulated by a bidirectional promoter (BDP) (named F/R-BDP). FOXM1 and RHNO1 each promote oncogenic phenotypes in HGSC cells, including clonogenic growth, DNA homologous recombination repair, and poly-ADP ribosylase inhibitor resistance. FOXM1 and RHNO1 are one of the first examples of oncogenic BDG, and therapeutic targeting of FOXM1/RHNO1 BDG is a potential therapeutic approach for ovarian and other cancers.
Keywords:
DNA repair; FOXM1; PARP inhibitors; RHNO1; bidirectional genes; cancer biology; chromosomes; gene expression; human; ovarian cancer.
© 2021, Barger et al.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Ataxia Telangiectasia Mutated Proteins / genetics
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Ataxia Telangiectasia Mutated Proteins / metabolism
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Carboplatin / pharmacology
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Carrier Proteins / genetics*
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Carrier Proteins / metabolism
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Cell Line, Tumor
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Cell Proliferation
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Checkpoint Kinase 1 / genetics
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Checkpoint Kinase 1 / metabolism
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Databases, Genetic
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Drug Resistance, Neoplasm
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Female
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Forkhead Box Protein M1 / genetics*
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Forkhead Box Protein M1 / metabolism
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Gene Expression Regulation, Neoplastic*
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Humans
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Neoplasms, Cystic, Mucinous, and Serous / drug therapy
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Neoplasms, Cystic, Mucinous, and Serous / genetics*
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Neoplasms, Cystic, Mucinous, and Serous / metabolism
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Neoplasms, Cystic, Mucinous, and Serous / pathology
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Ovarian Neoplasms / drug therapy
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Ovarian Neoplasms / genetics*
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Ovarian Neoplasms / metabolism
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Ovarian Neoplasms / pathology
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Poly(ADP-ribose) Polymerase Inhibitors / pharmacology
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Promoter Regions, Genetic
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Recombinational DNA Repair
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Signal Transduction
Substances
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Carrier Proteins
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FOXM1 protein, human
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Forkhead Box Protein M1
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Poly(ADP-ribose) Polymerase Inhibitors
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RHNO1 protein, human
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Carboplatin
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ATR protein, human
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Ataxia Telangiectasia Mutated Proteins
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CHEK1 protein, human
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Checkpoint Kinase 1
Associated data
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GEO/GSE150864
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GEO/GSE92332
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GEO/GSE72056