Defining the role of FOSL2 in molecular adaptation to hypoxia in colorectal cancer


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Eric VANCAUWENBERGHE1,Hannah Bolland1,Christopher Carroll1,Leonardo Da Motta1,Victoria Wright2,Nadine Holmes2,Francesca Buffa3,Anna Grabowska4,Adrian Harris5,Alan McIntyre6
1Hypoxia and Tumour Microenvironment Group, Cancer Biology, Division of Cancer and Stem Cells, University of Nottingham,2Deep Seq, School of Life Sciences, University of Nottingham,3Computational Biology and Integrative Genomics, Department of Oncology, University of Oxford,4Cancer Biology, Division of Cancer and Stem Cells, University of Nottingham,5Molecular Oncology Laboratories, Department of Oncology, The Weatherall Institute of Molecular Medicine, University of Oxford,6University of Nottingham

Abstract

Background

Colorectal cancer is the 3rd most common cancer worldwide. Low oxygen (hypoxia) found in roughly one third of colorectal cancer patients is associated with therapy resistance and poor patient outcome. Hypoxia stabilizes the transcription factors HIF1α and HIF2α which enable molecular adaptation at a transcriptional level to the hypoxic insult, in cooperation with additional transcription factors. We identified FOSL2 (FRA2), a subunit of the Activator protein 1 (AP-1) transcription factor, as a key mediator of hypoxic cell viability in an induced essentiality lentiviral shRNA screen in colorectal cancer. The aim of this project was to investigate the role of FOSL2 in molecular adaptation to hypoxia in colorectal cancer.

Method

Our experiments were conducted in a panel of cancer and normal colorectal cell lines in normoxia and hypoxia (1%O2). The association of FOSL2 with other AP1 subunits and the impact of FOSL2 on hypoxia-regulated expression and cell phenotypes was investigated using a variety of cell and molecular biology approaches.

Results

Our results identify that FOSL2 is upregulated by hypoxia in colorectal cancer in a HIF independent manner. Utilising 2D and 3D (spheroid) cultures, we observed that FOSL2 knockdown significantly decreased cancer cell survival in hypoxia but not in normoxia or in normal colon cells. In hypoxic conditions FOSL2 interacts with a selected pattern of other AP-1 subunits to mediate the transcriptional response to hypoxia. Ongoing RNA-seq studies will identify the FOSL2 regulated genes and the HIF-dependent and independent role for FOSL2 in hypoxic molecular adaptation.

Conclusion

Together, these data identify FOSL2 as a key mediator of the molecular adaptation to the hypoxic insult in the colorectal tumour microenvironment. FOSL2 is a likely therapeutic target for the treatment of the therapy resistant hypoxic regions of colorectal cancers.