The identification and validation of Trichosstatin A as a potential inhibitor of colon tumorigenesis and colon cancer stem-like cells.

Colon cancer is one of the most prevalent cancer types in developed countries. Metastasis and drug resistance are two contributing factors to the high mortality rate. Accumulating evidence suggest that cancer stem-like cells (CSCs) represents as a major contributor to these malignant features. Here, we identified and isolated colon cancer stem-like cells using side-population (SP) method from human colon cancer cell lines. SP colon cells demonstrate cancer stem-like cell properties including enhanced sphere-forming ability and resistance towards fluorouracil (5-FU). The CSC properties were associated with the increased expression level of major oncogenic and stem cell markers including β-catenin, NF-kB, Akt/mTOR, KRAS and c-Myc. Trichostatin A (TSA), an antifungal antibiotic also a HDAC inhibitor, was found to function not only to decrease the expression of oncogenic markers but also the colon CSC properties. Importantly, TSA and 5-FU combined treatment synergistically suppressed colon cancer viability. Finally, in vivo results demonstrated that TSA alone and in combination with 5-FU effectively suppressed colon tumorigenesis. Collectively, this study provides preclinical evidence that TSA may function as a potential colon cancer therapeutic agent by targeting CSC and overcoming 5-FU resistance.