HSF1 promotes the inhibition of EMT-associated migration by low glucose via directly regulating Snail1 expression in HCC cells.

OBJECTIVE: Reprogramming energy metabolism has been defined as the ninth hallmark of cancer; glucose deprivation might be a novel, feasible and effective approach for cancer treatment. However, the comprehensive illustration of behavior alteration of hepatocellular carcinoma (HCC) cells induced by glucose restriction is lacking and associated molecular mechanism is still unclear.

METHODS: Three human HCC cell lines were cultured with normal control (25.0 mM D-glucose) and low glucose (5.5 mM D-glucose) Dulbecco's modified Eagle's medium. Cell migration ability was assessed by both transwell migration assay and wound healing assay. Levels of heat shock factor 1 (HSF1) and epithelial-mesenchymal transition (EMT) markers, E-cadherin and N-cadherin, were estimated by real-time polymerase chain reaction and western blotting. Moreover, low glucose-induced inhibition of EMT-associated migration via the HSF1 was demonstrated in HCC cells by knocking down HSF1 with the HSF1 siRNA technique; in terms of molecular mechanism, direct regulation of HSF1 on snail1 expression was identified by chromatin immunoprecipitation followed by Luciferase reporter assay.

RESULTS: Herein, we showed that low glucose culture hampered typical EMT-like morphological change, "cadherin switching," and cell migration of HCC cells and further demonstrated that persistent down-regulation of HSF1 induced by glucose restriction, resulting in direct inhibition of snail1 expression and promoting the up-regulation of E-cadherin expression, and HSF1 was required for EMT-associated migration of HCC cells when cultured with low glucose media.

CONCLUSION: All these results illustrate that glucose restriction can repress the EMT and migration of HCC cells, and demonstrate the importance of HSF1 to our understanding on HCC treatment as a novel and effective therapeutic target or adjuvant strategy.