TCF12 Activates TGFB2 Expression to Promote the Malignant Progression of Melanoma

SIMPLE SUMMARY: Melanoma is the deadliest form of skin cancer, with the BRAF(V600E) mutation being the most prevalent driver mutation. Despite targeted therapies against BRAF(V600E) mutation and immune checkpoint-blocking antibodies providing treatment options for patients, the heterogeneous nature of melanoma significantly limits treatment efficacy. Understanding diverse regulatory mechanisms in melanoma will shed light on improving the current treatment modalities. In this study, we explored the function of a novel transcriptional activator, TCF12, in melanoma progression. We found that the expression level of TCF12 is elevated as melanoma progresses, and high expression is strongly associated with poor survival outcomes in melanoma patients. Functionally, TCF12 enhances melanoma proliferation and metastasis, as well as the sensitivity to BRAF(V600E)-targeted therapy. Mechanistically, TGFB2 is the direct transcriptional target of TCF12, mediating its pro-tumorigenic effects. Collectively, our study supported the oncogenic functions of TCF12 in melanoma, revealing it as a potential target to improve the efficacy of BRAF(V600E)-targeted therapy. ABSTRACT: As one of the most common malignant tumors, melanoma is a serious threat to human health. More than half of melanoma patients have a BRAF mutation, and 90% of them have a BRAF(V600E) mutation. There is a targeted therapy for patients using a BRAF(V600E) inhibitor. However, no response to treatment is generally inevitable due to the heterogeneity of melanoma. Coupled with its high metastatic character, melanoma ultimately leads to poor overall survival. This study aimed to explore the possible mechanisms of melanoma metastasis and identify a more effective method for the treatment of melanoma. In this paper, we report that TCF12 expression is higher in melanoma, especially in metastatic tumors, through analyzing data from TCGA. Then, cell proliferation, colony formation, and transwell assays show that the upregulated expression of TCF12 can promote proliferation and metastasis of melanoma cells in vitro. The same result is confirmed in the subcutaneous tumor formation assay. Moreover, TGFB2 is identified as a direct downstream target of TCF12 by RNA-seq, qPCR, immunoblotting, ChIP, and a dual luciferase reporting assay. Interestingly, depletion of TCF12 can sensitize melanoma to BRAF inhibition both in vitro and in vivo. Overall, our results demonstrate that TCF12 promotes melanoma progression and can be a potential tumor therapeutic target.