Suppression of alpha-tubulin acetylation potentiates therapeutic efficacy of Eribulin in liver cancer

Hepatocellular carcinoma (HCC) is a prevalent cancer with limited effective treatments. Eribulin mesylate is a novel chemotherapy drug that inhibits microtubule elongation and may impact the tumor microenvironment and immune pathway. This study aims to investigate the impact of changes in microtubule acetylation levels on HCC development and treatment outcomes. Clinical and molecular data were aggregated from databases, with survival analysis conducted to evaluate the relevance of microtubule acetylation. In vitro experiments using HCC cell lines and a tumor cell transplantation model in C57BL/c mice were performed to investigate the effects of microtubule acetylation on Eribulin treatment. A significant correlation was found between the level of lysine 40 acetylation of alpha-tubulin (acetyl-alpha-tubulin-lys40) and overall survival of HCC patients, with a better prognosis associated with a lower level of acetyl-alpha-tubulin-lys40. Knocking down ATAT1 or overexpressing HDAC6 reduced the level of acetyl alpha-tubulin-lys40 and sensitized Eribulin treatment both in vitro and in vivo. In summary, acetyl-alpha-tubulin-lys40 was increased in HCC and was associated with a shorter overall survival of HCC patients. Reducing the level of acetyl alpha-tubulin-lys40 can enhance sensitivity to Eribulin treatment both in vitro and in vivo, thereby establishing acetyl-alpha tubulin-lys40 as a potential prognostic marker and predictive indicator for Eribulin treatment in HCC patients.