Co-regulation and function of FOXM1/RHNO1 bidirectional genes in cancer
- University of Nebraska Medical Cancer, United States
- University of Nebraska Medical Center, United States
- Roswell Park Comprehensive Cancer Center, United States
- University of Pennsylvania Perelman School of Medicine, United States
- Massachusetts General Hospital Cancer Center, Harvard Medical School, United States
- University of Nebraska Medical Center;, United States
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 (RS) 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 (HR), and poly-ADP ribosylase (PARP) 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.
Data availability
All data generated are found within the manuscript and supporting files. sc-RNA-seq data is deposited in GEO.
Article and author information
Author details
Funding
National Institutes of Health (P30CA036727)
- Adam R Karpf
Rivkin Center for Ovarian Cancer
- Adam R Karpf
Fred & Pamela Pamela Buffett Cancer Center
- Adam R Karpf
UNMC Fellowship
- Carter J Barger
McKinsey Ovarian Cancer Research Fund
- Adam R Karpf
UNMC Core Facility Users Grant
- Adam R Karpf
National Institutes of Health (T32CA009476)
- Carter J Barger
National Institutes of Health (F99CA212470)
- Carter J Barger
National Institutes of Health (P50CA228991)
- Ronny Drapkin
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Reviewing Editor
- Lynne-Marie Postovit, University of Alberta, Canada
Version history
- Received: January 11, 2020
- Accepted: April 22, 2021
- Accepted Manuscript published: April 23, 2021 (version 1)
- Version of Record published: May 7, 2021 (version 2)
Copyright
© 2021, Barger et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Co-regulation and function of FOXM1/RHNO1 bidirectional genes in cancer
eLife 10:e55070.
https://doi.org/10.7554/eLife.55070
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