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.
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
Further reading
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- Cancer Biology
Background:
Cervical adenocarcinoma (ADC) is more aggressive compared to other types of cervical cancer (CC), such as squamous cell carcinoma (SCC). The tumor immune microenvironment (TIME) and tumor heterogeneity are recognized as pivotal factors in cancer progression and therapy. However, the disparities in TIME and heterogeneity between ADC and SCC are poorly understood.
Methods:
We performed single-cell RNA sequencing on 11 samples of ADC tumor tissues, with other 4 SCC samples served as controls. The immunochemistry and multiplexed immunofluorescence were conducted to validate our findings.
Results:
Compared to SCC, ADC exhibited unique enrichments in several sub-clusters of epithelial cells with elevated stemness and hyper-malignant features, including the Epi_10_CYSTM1 cluster. ADC displayed a highly immunosuppressive environment characterized by the enrichment of regulatory T cells (Tregs) and tumor-promoting neutrophils. The Epi_10_CYSTM1 cluster recruits Tregs via ALCAM-CD6 signaling, while Tregs reciprocally induce stemness in the Epi_10_CYSTM1 cluster through TGFβ signaling. Importantly, our study revealed that the Epi_10_CYSTM1 cluster could serve as a valuable predictor of lymph node metastasis for CC patients.
Conclusions:
This study highlights the significance of ADC-specific cell clusters in establishing a highly immunosuppressive microenvironment, ultimately contributing to the heightened aggressiveness and poorer prognosis of ADC compared to SCC.
Funding:
Funded by the National Natural Science Foundation of China (82002753; 82072882; 81500475) and the Natural Science Foundation of Hunan Province (2021JJ40324; 2022JJ70103).
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- Cancer Biology
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