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We have also uncovered a previously unknown mechanosensitive capability of the epigenetic regulator JMJD1a/KDM3A (See Publications; Kaukonen et al. 2016). JMJD1a is a histone demethylase that translocates from the cytoplasm to the nucleus when the cells are grown in cancerous ECM or other rigid environments. Nuclear and active JMJD1a promotes the expression of Hippo pathway transcriptional coactivators YAP/TAZ, driving proliferation. Currently we are interested in characterizing additional components of the mechanosensitive JMJD1a signaling pathway.
Introduction: Cell functions, such as migration and proliferation, are highly dependent on the mechanical properties of the cells’ environment. Cells probe the surrounding extracellular matrix (ECM) and respond to its stiffness and topographical cues by tuning proliferation, migration, gene expression and even their epigenetic landscape. Thus, mechanobiology is emerging as an important yet poorly understood area of cancer biology. The role of integrins as key cellular mechanosensors is well established, but the link between integrin activity regulation and mechanosensing remains poorly understood. Moreover, the process of converting mechanical signals into biochemical ones, i.e. mechanotransduction, has only partly been elucidated.
Our research: We are interested in understanding how the biophysical properties of the ECM affect integrin activity and, vice versa, to learn more about the crosstalk between cancer and the tumor microenvironment. We have recently shown that SHARPIN, an integrin activity inhibitor, is important in regulating collagen remodeling and that SHARPIN deficiency reduces traction forces applied on extracellular collagen (See Publications; Peuhu et al. 2017).
Integrins in focal adhesions couple the ECM to the actin cytoskeleton and mediate cellular force transmission. Mouse mammary gland stromal fibroblasts lacking SHARPIN (Sharpin -/-; middle panel) exert lower traction forces on a collagen matrix than wild-type cells (wt; left panel). Reintroduction of mCherry-SHARPIN rescues this defect (right panel). The ability of SHARPIN to inhibit integrin activity could represent an important regulatory step in focal adhesion dynamics and mechanotransduction. In these images, traction force maps are shown where the colour scale represents the magnitude of traction stresses in Pa and cell boundaries are indicated by dashed lines. Adapted from Peuhu et al. 2017.
A stiff environment, such as the tumour stroma, triggers the nuclear entry of histone demethylase JMJD1a. JMJD1a then demethylates the promoter of WWTR1 (TAZ), driving a proliferation-promoting transcriptional program (adapted from Kaukonen et al. 2016).