HDACIs and the inhibition of invasive potential

A major problem in the treatment of cancer and prolongation of patient survival is the dissemination of cells from a defined tumor site into a loco-regional disease and ultimately to full metastatic spread into distant organs. In the manuscript by Ierano et al. multiple chemically diverse histone deacetylase inhibitors (HDACIs) in tumor cell types of many diverse origins were shown to increase expression of the receptor CXCR4; a receptor whose expression promotes metastatic spread of tumor cells and that is correlated with a stage independent poor prognosis.(1,2) The ligand of CXCR4, CXCL12, also called stromal cell-derived factor (SDF1), stimulates signaling through multiple pathways downstream of the CXCR4 receptor including SRC kinases, ERK1/2, and STAT3. Inhibition of SRC, ERK, or STAT3 can all suppress tumor cell migration and reduce the threshold at which tumor cells undergo apoptosis.(3-8) The authors noted that despite increased CXCR4 expression following HDACI treatment, exogenous CXCL12 ligand had a reduced ability to stimulate cell signaling processes, with the phosphorylation of both SRC and STAT3 at activating sites declining. This resulted in less induced migration of HDACI-treated tumor cells. No studies were undertaken to determine whether HDACI-treated cells transduced to express activated forms of SRC or STAT3 or retained their invasive phenotype; however a loss of SRC and STAT3 signaling would predict for a less invasive phenotype.