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Focal Adhesion Kinase controls transcription via chromatin accessibility

A study led by CRUK Edinburgh Centre scientists provides the first demonstration that Focal Adhesion Kinase controls transcription via chromatin accessibility: January 2021

Focal Adhesion Kinase (FAK) is a cytoplasmic non-receptor protein tyrosine kinase involved in regulation of the cytoskeleton and synthesised by multiple cells of the human body. FAK is often overexpressed in cancer cells and is believed to play an important role in the progression of tumours to a malignant phenotype. Researchers in Edinburgh have been studying this protein for many years, providing some critical insights into its biological functions and roles in cancer. This included the seminal discovery that nuclear FAK can control expression of important genes and, through this process, help cancer cells to evade anti-tumour immunity (Cell. 2015;163:160-73).

In a recent study published in Scientific Reports and titled “FAK regulates IL-33 expression by controlling chromatin accessibility at c-Jun motifs”, the Edinburgh team, in collaboration with investigators from Glasgow, used a molecular biology technique called ATAC-seq (Assay for Transposase-Accessible Chromatin using sequencing) to assess chromatin accessibility across the genome. This approach revealed that FAK controls chromatin accessibility at a subset of regulated genes. FAK-dependent chromatin accessibility is linked to differential gene expression, including of the FAK-regulated cytokine and transcriptional regulator interleukin-33 (IL-33), which controls anti-tumour immunity. The work provides the first demonstration that FAK controls transcription via chromatin accessibility, identifying a novel mechanism by which nuclear FAK regulates biologically important gene expression.

The work was driven by Billie Griffith, a PhD student at the Cancer Research UK Edinburgh Centre, and Dr Rosie Upstill-Goddard, a bioinformatician in the Wolfson Wohl Cancer Research Centre in Glasgow. It was led by Dr Adam Byron and Prof Margaret Frame from the Cancer Research UK Edinburgh Centre and Dr Bryan Serrels from the Wolfson Wohl Cancer Research Centre, now with Nanostring Inc. The funding for the study was provided by Cancer Research UK.

The study not only provides important new insights into the biology of Focal Adhesion Kinase, but it could also aid development of FAK inhibitors (which are currently undergoing evaluation as anticancer agents) as clinically useful therapeutics.

Schematic model illustrating regulation of IL-33 expression by FAK.
Schematic model illustrating regulation of IL-33 expression by FAK [for details see Griffith et al. Sci Rep. 2021;11:229].

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