Background: Vemurafenib is a selective BRAF inhibitor with significant early effects in melanoma, but resistance will develop with the duration of treatment. Therefore, overcoming vemurafenib resistance can effectively improve the survival rate of melanoma. The transcriptional activity of TCF4  is necessary to maintain the malignant phenotype of cancer cells. However, the effect of TCF4  on melanoma sensitivity to vemurafenib and the underlying mechanism is unclear.
Methods: Vemurafenib-resistant A375 (A375/Vem) and SK-Mel-28 (SK-Mel-28/Vem) cells were constructed by administering increasing concentrations of vemurafenib, and the expression of TCF4  was examined in parent and vemurafenib-resistant cells. TCF4  loss-function cells models were established in A375/Vem and SK-Mel-28/Vem cells, respectively. Cell survival, clone formation, and cell apoptosis were assessed. The downstream target gene of TCF4  was verified by chromatin immunoprecipitation. Finally, the effect of TCF4  on melanoma cells glycolysis was investigated and were performed.
Results: TCF4  expression was increased in vemurafenib-resistant melanoma cells, and knocking down TCF4  could promote the sensitivity of melanoma cells to vemurafenib. Mechanism investigation revealed that TCF4  could interact with GLUT3  and silencing TCF4  could inhibit GLUT3  expression. In addition, overexpression of GLUT3  reversed the growth and glycolysis of tumor cells that were inhibited by TCF4  knockdown.
Conclusion: Our study demonstrates that TCF4  downregulation sensitizes melanoma cells to vemurafenib through inhibiting GLUT3 -mediated glycolysis. These findings support TCF4  as an oncogene and provide new mechanism by which TCF4  confers chemotherapy resistance in melanoma.
Keywords: melanoma, chemotherapy resistance, BRAF inhibitor, glucose transporter, transcription factor 4, Warburg effect