FOXD1 promotes dedifferentiation and targeted therapy resistance in melanoma by regulating the expression of connective tissue growth factor

Abstract

Metastatic melanoma is an aggressive skin cancer and associated with a poor prognosis. In clinical terms, targeted therapy is one of the most important treatments for patients with BRAF V600E -mutated advanced melanoma. However, the development of resistance to this treatment compromises its therapeutic success. We previously demonstrated that forkhead box D1 (FOXD1) regulates melanoma migration and invasion. Here, we found that FOXD1 was highly expressed in melanoma cells and was associated with a poor survival of patients with metastatic melanoma. Upregulation of FOXD1 expression enhanced melanoma cells' resistance to vemurafenib (BRAF inhibitor [BRAFi]) or vemurafenib and cobimetinib (MEK inhibitor) combination treatment whereas loss of FOXD1 increased the sensitivity to treatment. By comparing gene expression levels between FOXD1 knockdown (KD) and overexpressing (OE) cells, we identified the connective tissue growth factor (CTGF) as a downstream factor of FOXD1. Chromatin immunoprecipitation and luciferase assay demonstrated the direct binding of FOXD1 to the CTGF promoter. Similar to FOXD1, knockdown of CTGF increased the sensitivity of BRAFi-resistant cells to vemurafenib. FOXD1 KD cells treated with recombinant CTGF protein were less sensitive towards vemurafenib compared to untreated FOXD1 KD cells. Based on these findings, we conclude that FOXD1 might be a promising new diagnostic marker and a therapeutic target for the treatment of targeted therapy resistant melanoma.

Identification of Antitumor miR-30e-5p Controlled Genes; Diagnostic and Prognostic Biomarkers for Head and Neck Squamous Cell Carcinoma

“…Moreover, the knockdown of FOXD1 impairs the colony-forming abilities of oral cancer cells after radiation treatment [ 47 ]. Another study showed that upregulated FOXD1 contributed to melanoma cells’ resistance to vemurafenib via the recruited expression of connective tissue growth factor [ 48 ]. In gastric cancer (GC) cells, FOXD1 -AS1 expression induced FOXD1 translation, and these events enhanced GC cell progression and cisplatin resistance [ 49 ].…”

FOXD1 Is a Transcription Factor Important for Uveal Melanocyte Development and Associated with High-Risk Uveal Melanoma

“…However, in this article we provide proof that FOXD1 can reliably be used as a biomarker in UM. FOXD1 expression has been assessed in multiple cancer types and is often correlated to a poor prognosis [ 63 , 64 , 65 , 66 ]. In vitro and in vivo experiments elucidated FOXD1 as an oncogene involved in proliferation, dedifferentiation, migration, and radio- and chemoresistance [ 67 , 68 , 69 , 70 , 71 ].…”

“…Functional work on FOXD1 in cutaneous melanoma elucidated its capability to induce the expression of the tumor-specific isoform Rac Family Small GTPase 1B ( RAC1B ) to enhance melanoma migration and invasion [ 38 ]. Additionally, upon BRAF inhibitor treatment, FOXD1 was shown to directly bind the CTGF promoter to promote dedifferentiation and therapy resistance [ 64 ]. In line with published data on EMT, we assessed FOXD1 expression with known EMT inducers and repressors described in squamous cell carcinoma and cutaneous melanoma.…”

The Expression and Survival Significance of FOXD1 in Lung Squamous Cell Carcinoma: A Meta-Analysis, Immunohistochemistry Validation, and Bioinformatics Analysis

“…Moreover, FOXD1 promoted cell proliferation, migration and invasion in colorectal cancer cells by regulating the phosphorylation of ERK 1/2 pathway [ 22 ]. In melanoma, overexpression of FOXD1 enhanced drug resistance of melanoma cells [ 23 ]. Conversely, Woong Ju, et al reported that FOXD1, as a transcription regulating gene, was significantly downregulated in chemoresistant epithelial ovarian cancer [ 24 ].…”