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

被引:18
|
作者
Sun, Qian [1 ,2 ]
Novak, Daniel [1 ,2 ]
Hueser, Laura [1 ,2 ]
Poelchen, Juliane [1 ,2 ]
Wu, Huizi [1 ,2 ,3 ]
Granados, Karol [1 ,2 ,4 ]
Federico, Aniello [1 ,2 ]
Liu, Ke [1 ,2 ,5 ]
Steinfass, Tamara [1 ,2 ]
Vierthaler, Marlene [1 ,2 ]
Umansky, Viktor [1 ,2 ]
Utikal, Jochen [1 ,2 ]
机构
[1] German Canc Res Ctr, Skin Canc Unit, Heidelberg, Germany
[2] Ruprecht Karl Univ Heidelberg, Univ Med Ctr Mannheim, Dept Dermatol Venereol & Allergol, Mannheim, Germany
[3] Beijing Genom Inst, BGI Genom, Shenzhen, Peoples R China
[4] Univ Costa Rica UCR, Sch Med, Dept Biochem, San Jose, Costa Rica
[5] Huazhong Univ Sci & Technol, Union Hosp, Tongji Med Coll, Dept Gastrointestinal Surg, Wuhan, Peoples R China
关键词
dedifferentiation; FOXD1; melanoma; resistance; targeted therapy; BRAF INHIBITOR RESISTANCE; DRUG-RESISTANCE; BREAST-CANCER; NEURAL CREST; CELLS; MITF; CTGF; PROLIFERATION; TRANSCRIPTION; PIGMENT;
D O I
10.1002/ijc.33591
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
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.
引用
收藏
页码:657 / 674
页数:18
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