PMID- 33837564
OWN - NLM
STAT- MEDLINE
DCOM- 20210906
LR  - 20210906
IS  - 1097-0215 (Electronic)
IS  - 0020-7136 (Linking)
VI  - 149
IP  - 3
DP  - 2021 Aug 1
TI  - FOXD1 promotes dedifferentiation and targeted therapy resistance in melanoma by 
      regulating the expression of connective tissue growth factor.
PG  - 657-674
LID - 10.1002/ijc.33591 [doi]
AB  - 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.
CI  - (c) 2021 The Authors. International Journal of Cancer published by John Wiley & 
      Sons Ltd on behalf of UICC.
FAU - Sun, Qian
AU  - Sun Q
AD  - Skin Cancer Unit, German Cancer Research Center (DKFZ), Heidelberg, Germany.
AD  - Department of Dermatology, Venereology and Allergology, University Medical Center 
      Mannheim, Ruprecht Karl University of Heidelberg, Mannheim, Germany.
FAU - Novak, Daniel
AU  - Novak D
AD  - Skin Cancer Unit, German Cancer Research Center (DKFZ), Heidelberg, Germany.
AD  - Department of Dermatology, Venereology and Allergology, University Medical Center 
      Mannheim, Ruprecht Karl University of Heidelberg, Mannheim, Germany.
FAU - Huser, Laura
AU  - Huser L
AD  - Skin Cancer Unit, German Cancer Research Center (DKFZ), Heidelberg, Germany.
AD  - Department of Dermatology, Venereology and Allergology, University Medical Center 
      Mannheim, Ruprecht Karl University of Heidelberg, Mannheim, Germany.
FAU - Poelchen, Juliane
AU  - Poelchen J
AD  - Skin Cancer Unit, German Cancer Research Center (DKFZ), Heidelberg, Germany.
AD  - Department of Dermatology, Venereology and Allergology, University Medical Center 
      Mannheim, Ruprecht Karl University of Heidelberg, Mannheim, Germany.
FAU - Wu, Huizi
AU  - Wu H
AD  - Skin Cancer Unit, German Cancer Research Center (DKFZ), Heidelberg, Germany.
AD  - Department of Dermatology, Venereology and Allergology, University Medical Center 
      Mannheim, Ruprecht Karl University of Heidelberg, Mannheim, Germany.
AD  - BGI Genomics, Beijing Genomics Institute, Shenzhen, China.
FAU - Granados, Karol
AU  - Granados K
AD  - Skin Cancer Unit, German Cancer Research Center (DKFZ), Heidelberg, Germany.
AD  - Department of Dermatology, Venereology and Allergology, University Medical Center 
      Mannheim, Ruprecht Karl University of Heidelberg, Mannheim, Germany.
AD  - Department of Biochemistry, School of Medicine, University of Costa Rica (UCR), 
      San Jose, Costa Rica.
FAU - Federico, Aniello
AU  - Federico A
AD  - Skin Cancer Unit, German Cancer Research Center (DKFZ), Heidelberg, Germany.
AD  - Department of Dermatology, Venereology and Allergology, University Medical Center 
      Mannheim, Ruprecht Karl University of Heidelberg, Mannheim, Germany.
FAU - Liu, Ke
AU  - Liu K
AD  - Skin Cancer Unit, German Cancer Research Center (DKFZ), Heidelberg, Germany.
AD  - Department of Dermatology, Venereology and Allergology, University Medical Center 
      Mannheim, Ruprecht Karl University of Heidelberg, Mannheim, Germany.
AD  - Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, 
      Huazhong University of Science and Technology, Wuhan, China.
FAU - Steinfass, Tamara
AU  - Steinfass T
AD  - Skin Cancer Unit, German Cancer Research Center (DKFZ), Heidelberg, Germany.
AD  - Department of Dermatology, Venereology and Allergology, University Medical Center 
      Mannheim, Ruprecht Karl University of Heidelberg, Mannheim, Germany.
FAU - Vierthaler, Marlene
AU  - Vierthaler M
AD  - Skin Cancer Unit, German Cancer Research Center (DKFZ), Heidelberg, Germany.
AD  - Department of Dermatology, Venereology and Allergology, University Medical Center 
      Mannheim, Ruprecht Karl University of Heidelberg, Mannheim, Germany.
FAU - Umansky, Viktor
AU  - Umansky V
AUID- ORCID: 0000-0003-0259-1839
AD  - Skin Cancer Unit, German Cancer Research Center (DKFZ), Heidelberg, Germany.
AD  - Department of Dermatology, Venereology and Allergology, University Medical Center 
      Mannheim, Ruprecht Karl University of Heidelberg, Mannheim, Germany.
FAU - Utikal, Jochen
AU  - Utikal J
AUID- ORCID: 0000-0001-5316-0241
AD  - Skin Cancer Unit, German Cancer Research Center (DKFZ), Heidelberg, Germany.
AD  - Department of Dermatology, Venereology and Allergology, University Medical Center 
      Mannheim, Ruprecht Karl University of Heidelberg, Mannheim, Germany.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20210506
PL  - United States
TA  - Int J Cancer
JT  - International journal of cancer
JID - 0042124
RN  - 0 (Azetidines)
RN  - 0 (Biomarkers, Tumor)
RN  - 0 (CCN2 protein, human)
RN  - 0 (FOXD1 protein, human)
RN  - 0 (Forkhead Transcription Factors)
RN  - 0 (Piperidines)
RN  - 139568-91-5 (Connective Tissue Growth Factor)
RN  - 207SMY3FQT (Vemurafenib)
RN  - ER29L26N1X (cobimetinib)
SB  - IM
MH  - Antineoplastic Combined Chemotherapy Protocols/*pharmacology
MH  - Apoptosis
MH  - Azetidines/administration & dosage
MH  - Biomarkers, Tumor/genetics/metabolism
MH  - *Cell Dedifferentiation
MH  - Cell Proliferation
MH  - Connective Tissue Growth Factor/genetics/*metabolism
MH  - *Drug Resistance, Neoplasm
MH  - Forkhead Transcription Factors/genetics/*metabolism
MH  - *Gene Expression Regulation, Neoplastic
MH  - Humans
MH  - Melanoma/*drug therapy/genetics/metabolism/pathology
MH  - Molecular Targeted Therapy
MH  - Mutation
MH  - Piperidines/administration & dosage
MH  - Prognosis
MH  - Signal Transduction
MH  - Survival Rate
MH  - Tumor Cells, Cultured
MH  - Vemurafenib/administration & dosage
OTO - NOTNLM
OT  - FOXD1
OT  - dedifferentiation
OT  - melanoma
OT  - resistance
OT  - targeted therapy
EDAT- 2021/04/11 06:00
MHDA- 2021/09/07 06:00
CRDT- 2021/04/10 06:05
PHST- 2021/03/22 00:00 [revised]
PHST- 2020/12/23 00:00 [received]
PHST- 2021/03/26 00:00 [accepted]
PHST- 2021/04/11 06:00 [pubmed]
PHST- 2021/09/07 06:00 [medline]
PHST- 2021/04/10 06:05 [entrez]
AID - 10.1002/ijc.33591 [doi]
PST - ppublish
SO  - Int J Cancer. 2021 Aug 1;149(3):657-674. doi: 10.1002/ijc.33591. Epub 2021 May 6.