Co-regulation and functional cooperativity of FOXM1 and RHNO1 bidirectional genes in ovarian cancer
SummaryWe report that the oncogenic transcription factorFOXM1is arranged in a head-to-head configuration withRHNO1, a gene involved in the ATR/CHK1-dependent DNA replication stress (DRS) response.FOXM1andRHNO1are both amplified and upregulated in high-grade serous ovarian cancer (HGSC).FOXM1andRHNO1expression 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.