Silencing TCF4 Sensitizes Melanoma Cells to Vemurafenib Through Inhibiting GLUT3-Mediated Glycolysis.

Abstract

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.

• Authors: Can Liu, Siqi He, Jianfei Zhang, Shiyan Li, Jian Chen, Chaofei Han
• Journal: OncoTargets and therapy (Onco Targets Ther) Vol. 13 Pg. 4905-4915 ( 2020) ISSN: 1178-6930 [Print] New Zealand
• PMID: 32581551 (Publication Type: Journal Article)
• Copyright: © 2020 Liu et al.