Overexpression of FRA1 (FOSL1) Leads to Global Transcriptional Perturbations, Reduced Cellular Adhesion and Altered Cell Cycle Progression

Wuroud Al-Khayyat; Jake Pirkkanen; Jessica Dougherty; Taylor Laframboise; Noah Dickinson; Neelam Khaper; Simon J Lees; Marc S Mendonca; Douglas R Boreham; Tze Chun Tai; Christopher Thome; Sujeenthar Tharmalingam

doi:10.3390/cells12192344

Overexpression of FRA1 (FOSL1) Leads to Global Transcriptional Perturbations, Reduced Cellular Adhesion and Altered Cell Cycle Progression

Cells. 2023 Sep 24;12(19):2344. doi: 10.3390/cells12192344.

Authors

Wuroud Al-Khayyat^{1

2}, Jake Pirkkanen², Jessica Dougherty², Taylor Laframboise², Noah Dickinson¹, Neelam Khaper^{3

4}, Simon J Lees^{3

4}, Marc S Mendonca^{5

6}, Douglas R Boreham^{1

2}, Tze Chun Tai^{1

2

7}, Christopher Thome^{1

2

7}, Sujeenthar Tharmalingam^{1

2

7}

Affiliations

¹ School of Natural Sciences, Laurentian University, Sudbury, ON P3E 2C6, Canada.
² Medical Sciences Division, NOSM University, 935 Ramsey Lake Rd., Sudbury, ON P3E 2C6, Canada.
³ Medical Sciences Division, NOSM University, 955 Oliver Rd., Thunder Bay, ON P7B 5E1, Canada.
⁴ Department of Biology, Lakehead University, Thunder Bay, ON P7B 5E1, Canada.
⁵ Department of Radiation Oncology, Radiation and Cancer Biology Laboratories, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
⁶ Department of Medical & Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
⁷ Health Sciences North Research Institute, Sudbury, ON P3E 2H2, Canada.

Abstract

FRA1 (FOSL1) is a transcription factor and a member of the activator protein-1 superfamily. FRA1 is expressed in most tissues at low levels, and its expression is robustly induced in response to extracellular signals, leading to downstream cellular processes. However, abnormal FRA1 overexpression has been reported in various pathological states, including tumor progression and inflammation. To date, the molecular effects of FRA1 overexpression are still not understood. Therefore, the aim of this study was to investigate the transcriptional and functional effects of FRA1 overexpression using the CGL1 human hybrid cell line. FRA1-overexpressing CGL1 cells were generated using stably integrated CRISPR-mediated transcriptional activation, resulting in a 2-3 fold increase in FRA1 mRNA and protein levels. RNA-sequencing identified 298 differentially expressed genes with FRA1 overexpression. Gene ontology analysis showed numerous molecular networks enriched with FRA1 overexpression, including transcription-factor binding, regulation of the extracellular matrix and adhesion, and a variety of signaling processes, including protein kinase activity and chemokine signaling. In addition, cell functional assays demonstrated reduced cell adherence to fibronectin and collagen with FRA1 overexpression and altered cell cycle progression. Taken together, this study unravels the transcriptional response mediated by FRA1 overexpression and establishes the role of FRA1 in adhesion and cell cycle progression.

Keywords: AP-1; CGL1; CRISPR activation; FOSL1; FRA-1; FRA1; adhesion; cell cycle; transcription factor; transcriptomics.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Cell Division
Cell Line
Gene Expression Regulation
Humans
Proto-Oncogene Proteins c-fos* / genetics
Proto-Oncogene Proteins c-fos* / metabolism
Transcription Factor AP-1* / genetics
Transcription Factor AP-1* / metabolism

Substances

Proto-Oncogene Proteins c-fos
Transcription Factor AP-1
fos-related antigen 1

Grants and funding

This research was funded by the following agencies and grants: (1) Natural Sciences and Engineering Research Council of Canada (NSERC) Collaborative Research and Development in partnership with Bruce Power and the Nuclear Innovation Institute, (2) NSERC Discovery Grant, (3) Northern Cancer Foundation, (4) Northern Ontario School of Medicine University Faculty Association Research Development Award, (5) Canada Graduate Scholarships—Master’s program, and (6) Ontario Graduate Scholarship.