<p>Silencing <em>TCF4</em> Sensitizes Melanoma Cells to Vemurafenib Through Inhibiting <em>GLUT3</em>-Mediated Glycolysis</p>

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.

Immune escape and metastasis mechanisms in melanoma: breaking down the dichotomy

“…In vemurafenib resistant cell lines, TCF4 knockdown sensitized melanoma cells to vemurafenib in a Glucose transporter 3 (GLUT3)-dependent manner, thereby decreasing lactate production. TCF4 inactivity has also been shown to be responsible for downregulation of metastatically-related genes ( 156 ). Given the acidifying role of lactate in the TME, it is unsurprising another study found TCF4 is enriched in “mesenchymal-like” cells and a suppressor of antigen-presentation programs.…”

Zinc finger proteins and ATP‐binding cassette transporter‐dependent multidrug resistance

“…36 The TCF4-expressing tumours develop EMT behaviours, associated with glycolysis-related chemoresistance traits in cancers, such as skin cancer. 37 FOXC2 plays a key role in developing cancer stem-cell features, but the effectiveness of FOXC2-related EMT inhibition in restoring drug sensitivity in cancer cells through animal models remains controversial. 38 Several oncogenic effectors induce signalling pathways mediating EMT, including hypoxia, fibroblast growth factor, epidermal growth factor [EGF], 39 phosphatidylinositol-3-kinase [PI3K]/Ak strain transforming [Akt] axis, 5′ AMP-activated protein kinase, Wnt, nuclear factor kappa-light-chain-enhancer of activated B cells [NF-кB], and Hedgehog [Hh].…”

“…The TCF4 belongs to the T‐cell factor/lymphoid enhancer family, a well‐known promoter of the Wingless/Integrated (Wnt)/β‐catenin pathway, which maintains the malignant phenotypes of cancer cells 36 . The TCF4 ‐expressing tumours develop EMT behaviours, associated with glycolysis‐related chemoresistance traits in cancers, such as skin cancer 37 . FOXC2 plays a key role in developing cancer stem‐cell features, but the effectiveness of FOXC2‐related EMT inhibition in restoring drug sensitivity in cancer cells through animal models remains controversial 38 …”