Targeting AP-1 transcription factors by CRISPR in the prostate
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Maria Riedel1, Huiqiang Cai1, Iben C. Stoltze2, Mikkel H. Vendelbo2,3, Erwin F. Wagner4,5, Latifa Bakiri5 and Martin K. Thomsen2,6
1 Department of Clinical Medicine, Aarhus University, Aarhus, Denmark
2 Department of Biomedicine, Aarhus University, Aarhus, Denmark
3 Department of Nuclear Medicine & PET Centre, Aarhus University Hospital, Aarhus, Denmark
4 Laboratory Genes and Disease, Department of Dermatology, Medical University of Vienna (MUV), Vienna, Austria
5 Laboratory Genes and Disease, Department of Laboratory Medicine, Medical University of Vienna (MUV), Vienna, Austria
6 Aarhus Institute of Advanced Studies (AIAS), Aarhus University, Aarhus, Denmark
|Martin K. Thomsen,||email:||[email protected]|
Keywords: AP-1; prostate cancer; CRISPR; mouse models; AAV
Received: June 02, 2021 Accepted: June 07, 2021 Published: September 14, 2021
Prostate cancer is the second most diagnosed cancer in men. It is a slow progressing cancer, but when the disease reaches an advanced stage, treatment options are limited. Sequencing analyses of cancer samples have identified genes that can potentially drive disease progression. We implemented the CRISPR/Cas9 technology to simultaneously manipulate multiple genes in the murine prostate and thus to functionally test putative cancer driver genes in vivo. The activating protein-1 (AP-1) transcription factor is associated with many different cancer types, with the proto-oncogenes JUN and FOS being the two most intensely studied subunits. We analyzed expression of FOS and JUNB in human prostate cancer datasets and observed decreased expression in advanced stages. By applying CRISPR/Cas9 technology, the role of these two transcription factors in prostate cancer progression was functionally tested. Our data revealed that loss of either JunB or Fos in the context of Pten loss drives prostate cancer progression to invasive disease. Furthermore, loss of Fos increases Jun expression, and CRISPR inactivation of Jun in this context decreases cell proliferation. Overall, these in vivo studies reveal that JunB and Fos exhibit a tumor suppressor function by repressing invasive disease, whereas Jun is oncogenic and increases cell proliferation. This demonstrates that AP-1 factors are implicated in prostate cancer progression at different stages and display a dual function as tumor suppressor and as an oncogene in cancer progression.
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