FHL1 Confers Human Hepatocellular Carcinoma Cells Resistant To Taxol Through Inhibition Of Microtubule Formation

Liver cancer is one of the common malignant tumors, ranking at the third position in occurrence among digestive tract tumors. Research has showed that FHL1 (the four-and-a-half LIM 1) belongs to the FHL family, and functions as tumor suppressor gene in liver cancer. The aim of our study is to further investigate the role of FHL1 in liver cancer, which will provide clues for treatment of liver cancer. Using co-immunoprecipitation and two-dimensional electrophoresis, we found a novel FHL1-interacting protein β-tubulin. Microtubules are composed of α/β-tubulin heterodimer. The a and P tubulin shares 40% amino acid sequence identity. Our study found that FHL1 interacted with a-tubulin both in vitro and in vivo, and regulated the acetylation of a-tubulin. The acetylation level of a-tubulin is a sign of stability of microtubule. Microtubule assembly experiment in vitro showed that FHLl inhibited the microtubule assembly. Moreover, the over-expression of FHL1 caused the HepG2 cells resistant to taxol. Further study showed that the expression of FHL1 was induced by taxol and H2O2. The affinity between the microtubule-associated protein Tau and microtubules is decreased through FHL1 activating the p38 signal pathway, which inhibited the microtubule assembly and caused the HepG2 cells resistant to taxol. For the first time, this study used microtubule, a key chemotherapy target, as a breakthrough point to investigate the role of FHL1 in taxol resistance and the molecular mechanism, which will be meaningful to the therapy and prognosis of liver cancer.