Hypoxia-inducible factor-1-dependent repression of E-cadherin in von Hippel-Lindau tumor suppressor-null renal cell carcinoma mediated by TCF3, ZFHX1A, and ZFHX1B.
A critical event in the pathogenesis of invasive and metastatic cancer is E-cadherin loss of function. Renal clear cell carcinoma (RCC) is characterized by loss of function of the von Hippel-Lindau tumor suppressor (VHL), which negatively regulates hypoxia-inducible factor-1 (HIF-1). Loss of E-cadherin expression and decreased cell-cell adhesion in VHL-null RCC4 cells were corrected by enforced expression of VHL, a dominant-negative HIF-1alpha mutant, or a short hairpin RNA directed against HIF-1alpha. In human RCC biopsies, expression of E-cadherin and HIF-1alpha was mutually exclusive. The expression of mRNAs encoding TCF3, ZFHX1A, and ZFHX1B, which repress E-cadherin gene transcription, was increased in VHL-null RCC4 cells in a HIF-1-dependent manner. Thus, HIF-1 contributes to the epithelial-mesenchymal transition in VHL-null RCC by indirect repression of E-cadherin.
Krishnamachary
Balaji
B
Vascular Biology Program, Institute for Cell Engineering, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA.
Zagzag
David
D
Nagasawa
Hideko
H
Rainey
Karin
K
Okuyama
Hiroaki
H
Baek
Jin H
JH
Semenza
Gregg L
GL
D051792:Basic Helix-Loop-Helix Proteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D001706:Biopsy; D015820:Cadherins / Q000096:biosynthesis* / Q000235:genetics; D002292:Carcinoma, Renal Cell / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D002448:Cell Adhesion / Q000502:physiology; D015536:Down-Regulation; D004847:Epithelial Cells / Q000473:pathology; D015972:Gene Expression Regulation, Neoplastic; D018398:Homeodomain Proteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D006801:Humans; D051793:Hypoxia-Inducible Factor 1 / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D007150:Immunohistochemistry; D007680:Kidney Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D008648:Mesoderm / Q000473:pathology; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D012097:Repressor Proteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D014157:Transcription Factors / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D014158:Transcription, Genetic; D051794:Von Hippel-Lindau Tumor Suppressor Protein / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D000074165:Zinc Finger E-box Binding Homeobox 2; D000071799:Zinc Finger E-box-Binding Homeobox 1
D051792:Basic Helix-Loop-Helix Proteins; D015820:Cadherins; D018398:Homeodomain Proteins; D051793:Hypoxia-Inducible Factor 1; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D012097:Repressor Proteins; D014157:Transcription Factors; D051794:Von Hippel-Lindau Tumor Suppressor Protein; D000074165:Zinc Finger E-box Binding Homeobox 2; D000071799:Zinc Finger E-box-Binding Homeobox 1; C407909:TCF3 protein, human; C486307:ZEB1 protein, human; C492363:ZEB2 protein, human