Co-regulation and function of FOXM1/RHNO1 bidirectional genes in cancer

  1. Carter J Barger
  2. Linda Chee
  3. Mustafa Albahrani
  4. Catalina Munoz-Trujillo
  5. Lidia Boghean
  6. Connor Branick
  7. Kunle Odunsi
  8. Ronny Drapkin
  9. Lee Zou
  10. Adam R Karpf  Is a corresponding author
  1. University of Nebraska Medical Cancer, United States
  2. University of Nebraska Medical Center, United States
  3. Roswell Park Comprehensive Cancer Center, United States
  4. University of Pennsylvania Perelman School of Medicine, United States
  5. Massachusetts General Hospital Cancer Center, Harvard Medical School, United States
  6. 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.

The following previously published data sets were used
    1. Ann-Marie Patch 1
    2. Elizabeth L Christie 2
    3. Dariush Etemadmoghadam 3
    4. Dale W Garsed 2
    5. Joshy George 4
    6. Sian Fereday 2
    7. Katia Nones 1
    8. Prue Cowin 2
    9. Kathryn Alsop 2
    10. Peter J Bailey 5
    11. Karin S Kassahn 6
    12. Felicity Newell 7
    13. Michael C J Quinn 1
    14. Stephen Kazakoff 1
    15. Kelly Quek 7
    16. Charlotte Wilhelm-Benartzi 8
    17. Ed Curry 8
    18. Huei San Leong 2
    19. Australian Ovarian Cancer Study Group; Anne Hamilton 9
    20. Linda Mileshkin 10
    21. George Au-Yeung 2
    22. Catherine Kennedy 11
    23. Jillian Hung 11
    24. Yoke-Eng Chiew 11
    25. Paul Harnett 12
    26. Michael Friedlander 13
    27. Michael Quinn 14
    28. Jan Pyman 14
    29. Stephen Cordner 15
    30. Patricia O'Brien 15
    31. Jodie Leditschke 15
    32. Greg Young 15
    33. Kate Strachan 15
    34. Paul Waring 16
    35. Walid Azar 2
    36. Chris Mitchell 2
    37. Nadia Traficante 2
    38. Joy Hendley 2
    39. Heather Thorne 2
    40. Mark Shackleton 10
    41. David K Miller 7
    42. Gisela Mir Arnau 2
    43. Richard W Tothill 10
    44. Timothy P Holloway 2
    45. Timothy Semple 2
    46. Ivon Harliwong 7
    47. Craig Nourse 7
    48. Ehsan Nourbakhsh 7
    49. Suzanne Manning 7
    50. Senel Idrisoglu 7
    51. Timothy J C Bruxner 7
    52. Angelika N Christ 7
    53. Barsha Poudel 7
    54. Oliver Holmes 1
    55. Matthew Anderson 7
    56. Conrad Leonard 1
    57. Andrew Lonie 17
    58. Nathan Hall 18
    59. Scott Wood 1
    60. Darrin F Taylor 7
    61. Qinying Xu 1
    62. J Lynn Fink 7
    63. Nick Waddell 7
    64. Ronny Drapkin 19
    65. Euan Stronach 8
    66. Hani Gabra 8
    67. Robert Brown 8
    68. Andrea Jewell 20
    69. Shivashankar H Nagaraj 7
    70. Emma Markham 7
    71. Peter J Wilson 7
    72. Jason Ellul 2
    73. Orla McNally 11
    74. Maria A Doyle 2
    75. Ravikiran Vedururu 2
    76. Collin Stewart 21
    77. Ernst Lengyel 20
    78. John V Pearson 1
    79. Nicola Waddell 1
    80. Anna deFazio 11
    81. Sean M Grimmond 5
    82. David D L Bowtell
    (2015) HGSC RNA-seq
    EGAD00001000877.

Article and author information

Author details

  1. Carter J Barger

    Eppley Institute, University of Nebraska Medical Cancer, Omaha, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Linda Chee

    Eppley Institute, University of Nebraska Medical Center, Omaha, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Mustafa Albahrani

    Eppley Institute, University of Nebraska Medical Center, Omaha, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Catalina Munoz-Trujillo

    Eppley Institute, University of Nebraska Medical Center, Omaha, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Lidia Boghean

    Eppley Institute, University of Nebraska Medical Center, Omaha, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Connor Branick

    Eppley Institute, University of Nebraska Medical Center, Omaha, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. Kunle Odunsi

    Gynecologic Oncology, Roswell Park Comprehensive Cancer Center, Buffalo, United States
    Competing interests
    The authors declare that no competing interests exist.
  8. Ronny Drapkin

    University of Pennsylvania Perelman School of Medicine, Philadelphia, United States
    Competing interests
    The authors declare that no competing interests exist.
  9. Lee Zou

    Massachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, United States
    Competing interests
    The authors declare that no competing interests exist.
  10. Adam R Karpf

    Eppley Institute, University of Nebraska Medical Center;, Omaha, United States
    For correspondence
    adam.karpf@unmc.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-0866-0666

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

  1. Lynne-Marie Postovit, University of Alberta, Canada

Publication history

  1. Received: January 11, 2020
  2. Accepted: April 22, 2021
  3. Accepted Manuscript published: April 23, 2021 (version 1)
  4. 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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  1. Carter J Barger
  2. Linda Chee
  3. Mustafa Albahrani
  4. Catalina Munoz-Trujillo
  5. Lidia Boghean
  6. Connor Branick
  7. Kunle Odunsi
  8. Ronny Drapkin
  9. Lee Zou
  10. Adam R Karpf
(2021)
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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