The transcriptional repressor ZEB1 promotes metastasis and loss of cell polarity in cancer.
Invasion and metastasis are the hallmarks of malignant tumor progression and the main cause of death in cancer. The embryonic program "epithelial-mesenchymal transition" (EMT) is thought to trigger invasion by allowing tumor cell dissemination. Here, we describe that the EMT-inducing transcriptional repressor ZEB1 promotes colorectal cancer cell metastasis and loss of cell polarity. Thereby, ZEB1 suppresses the expression of cell polarity factors, in particular of Lgl2, which we found reduced in colorectal and breast cancers. We further show that retention of Lgl2 expression is critical for the epithelial phenotype and that its loss might be involved in metastasis. Thus, by linking EMT, loss of polarity, and metastasis, ZEB1 is a crucial promoter of malignant tumor progression.
Spaderna
Simone
S
Department of Visceral Surgery, University of Freiburg, Freiburg, Germany.
Schmalhofer
Otto
O
Wahlbuhl
Mandy
M
Dimmler
Arno
A
Bauer
Katja
K
Sultan
Aneesa
A
Hlubek
Falk
F
Jung
Andreas
A
Strand
Dennis
D
Eger
Andreas
A
Kirchner
Thomas
T
Behrens
Jürgen
J
Brabletz
Thomas
T
D000818:Animals; D001483:Base Sequence; D001943:Breast Neoplasms / Q000473:pathology*; D002277:Carcinoma / Q000473:pathology*; D016764:Cell Polarity / Q000235:genetics*; D015179:Colorectal Neoplasms / Q000473:pathology*; D015972:Gene Expression Regulation, Neoplastic; D045325:HCT116 Cells; D018398:Homeodomain Proteins / Q000037:antagonists & inhibitors / Q000502:physiology*; D006801:Humans; D008113:Liver Neoplasms / Q000556:secondary; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008969:Molecular Sequence Data; D009362:Neoplasm Metastasis; D009368:Neoplasm Transplantation; D034622:RNA Interference / Q000502:physiology; D012097:Repressor Proteins / Q000037:antagonists & inhibitors / Q000502:physiology; D012689:Sequence Homology, Nucleic Acid; D014157:Transcription Factors / Q000037:antagonists & inhibitors / Q000502:physiology*; D014183:Transplantation, Heterologous; D000071799:Zinc Finger E-box-Binding Homeobox 1; D028961:beta Karyopherins / Q000235:genetics
D018398:Homeodomain Proteins; D012097:Repressor Proteins; D014157:Transcription Factors; C486307:ZEB1 protein, human; D000071799:Zinc Finger E-box-Binding Homeobox 1; D028961:beta Karyopherins; C424163:late gestation lung 2 karyopherin