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

Carter J Barger,Linda Chee,Kunle Odunsi,Lee Zou,Adam R Karpf,Ronny Drapkin,Mustafa Albahrani,Catalina Munoz-Trujillo,Lidia Boghean,Connor Branick

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.

Highlights

The forkhead/winged helix domain transcription factor FOXM1 promotes cancer by transactivating genes with oncogenic potential (Halasi and Gartel, 2013a; Kalathil et al, 2020)
We show that FOXM1 and RHNO1 both contribute to several important high-grade serous carcinoma (HGSC) cell phenotypes, including clonogenic growth and cell survival, DNA homologous recombination repair (HR) repair, and PARP inhibitor (PARPi) resistance
FOXM1 is located at chromosome 12p13.33, a region showing frequent copy number gains in HGSC, and amplification at this locus is associated with reduced patient survival (Barger et al, 2019; Barger et al, 2015)

Summary

Introduction

The forkhead/winged helix domain transcription factor FOXM1 promotes cancer by transactivating genes with oncogenic potential (Halasi and Gartel, 2013a; Kalathil et al, 2020). High-grade serous ovarian cancer, known as high-grade serous carcinoma (HGSC), is the most common and deadly subtype of epithelial ovarian cancer (EOC) (Bowtell et al, 2015). Molecular features of this tumor type include ubiquitous TP53 mutations, defects in DNA homologous recombination repair (HR), BRCA gene mutations, and robust genomic instability characterized by widespread copy number alterations (CNAs) (The Cancer Genome Atlas Research Network, 2011).

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