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bioRxiv · 10.1101/630442

Co-regulation and functional cooperativity of FOXM1 and RHNO1 bidirectional genes in ovarian cancer

Barger, C. J.·Branick, C.·Chee, L.·Albahrani, M.·Klinkebiel, D.·Drapkin, R.·Odunsi, K.·Zou, L.·Karpf, A.
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Abstract

We report that the oncogenic transcription factor FOXM1 is arranged in a head-to-head configuration with RHNO1, a gene involved in the ATR/CHK1-dependent DNA replication stress (DRS) response. FOXM1 and RHNO1 are both amplified and upregulated in high-grade serous ovarian cancer (HGSC). FOXM1 and RHNO1 expression are closely associated in normal and cancer tissues, including single cells, and a bidirectional promoter (F/R-BDP) mediates balanced expression. Targeting of FOXM1 and RHNO1 in HGSC cells using shRNA, CRISPR mutagenesis, or CRISPR interference directed to the F/R-BDP reduced DNA homologous recombination repair (HR) capacity, increased DNA damage, reduced clonogenic survival, and sensitized HGSC cells to the poly-ADP ribosylase inhibitor (PARPi) olaparib. Thus, there is functional cooperativity between FOXM1 and RHNO1 in cancer cells, and combinatorial targeting of this bidirectional gene pair may be a novel cancer therapeutic strategy. More broadly, our data provide evidence that bidirectional gene units function in human cancer.

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Barger, C. J., Branick, C., Chee, L., Albahrani, M., Klinkebiel, D., Drapkin, R., Odunsi, K., Zou, L., Karpf, A.. 2019-05-07. Co-regulation and functional cooperativity of FOXM1 and RHNO1 bidirectional genes in ovarian cancer. https://doi.org/10.1101/630442

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