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

Elife. 2021 Apr 23:10:e55070. doi: 10.7554/eLife.55070.

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 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, 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.

Keywords: DNA repair; FOXM1; PARP inhibitors; RHNO1; bidirectional genes; cancer biology; chromosomes; gene expression; human; ovarian cancer.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Ataxia Telangiectasia Mutated Proteins / genetics
  • Ataxia Telangiectasia Mutated Proteins / metabolism
  • Carboplatin / pharmacology
  • Carrier Proteins / genetics*
  • Carrier Proteins / metabolism
  • Cell Line, Tumor
  • Cell Proliferation
  • Checkpoint Kinase 1 / genetics
  • Checkpoint Kinase 1 / metabolism
  • Databases, Genetic
  • Drug Resistance, Neoplasm
  • Female
  • Forkhead Box Protein M1 / genetics*
  • Forkhead Box Protein M1 / metabolism
  • Gene Expression Regulation, Neoplastic*
  • Humans
  • Neoplasms, Cystic, Mucinous, and Serous / drug therapy
  • Neoplasms, Cystic, Mucinous, and Serous / genetics*
  • Neoplasms, Cystic, Mucinous, and Serous / metabolism
  • Neoplasms, Cystic, Mucinous, and Serous / pathology
  • Ovarian Neoplasms / drug therapy
  • Ovarian Neoplasms / genetics*
  • Ovarian Neoplasms / metabolism
  • Ovarian Neoplasms / pathology
  • Poly(ADP-ribose) Polymerase Inhibitors / pharmacology
  • Promoter Regions, Genetic
  • Recombinational DNA Repair
  • Signal Transduction

Substances

  • Carrier Proteins
  • FOXM1 protein, human
  • Forkhead Box Protein M1
  • Poly(ADP-ribose) Polymerase Inhibitors
  • RHNO1 protein, human
  • Carboplatin
  • ATR protein, human
  • Ataxia Telangiectasia Mutated Proteins
  • CHEK1 protein, human
  • Checkpoint Kinase 1

Associated data

  • GEO/GSE150864
  • GEO/GSE92332
  • GEO/GSE72056