Eppley Institute for Cancer Research and Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, United States.
Departments of Gynecologic Oncology, Immunology, and Center for Immunotherapy, Roswell Park Comprehensive Cancer Center, Buffalo, United States.
Elife. 2021 Apr 23;10:e55070. doi: 10.7554/eLife.55070.
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 is co-amplified and co-expressed with , a gene involved in the ATR-Chk1 signaling pathway that functions in the DNA replication stress response. We demonstrate that and 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.
叉头框蛋白 M1（FOXM1）转录因子是一种癌蛋白，也是人类癌症中预后不良的重要生物标志物。FOXM1 的过表达和激活在高级别浆液性卵巢癌（HGSC）中很常见，HGSC 是最常见且致命的卵巢癌形式，与染色体 12p13.33 的拷贝数增加有关。我们发现，在参与 ATR-Chk1 信号通路的基因 和 中，FOXM1 与 共扩增和共表达，该基因在 DNA 复制应激反应中发挥作用。我们证明 和 是由双向启动子（BDP）（命名为 F/R-BDP）调控的头对头（即双向）基因（BDG）。FOXM1 和 RHNO1 均可促进 HGSC 细胞的致癌表型，包括集落形成、DNA 同源重组修复和多聚 ADP 核糖酶抑制剂耐药性。FOXM1 和 RHNO1 是第一个致癌 BDG 例子之一，靶向 FOXM1/RHNO1 BDG 的治疗可能是卵巢癌和其他癌症的潜在治疗方法。
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