The TWIST/Mi2/NuRD protein complex and its essential role in cancer metastasis.
The epithelial-mesenchymal transition (EMT) converts epithelial tumor cells into invasive and metastatic cancer cells, leading to mortality in cancer patients. Although TWIST is a master regulator of EMT and metastasis for breast and other cancers, the mechanisms responsible for TWIST-mediated gene transcription remain unknown. In this study, purification and characterization of the TWIST protein complex revealed that TWIST interacts with several components of the Mi2/nucleosome remodeling and deacetylase (Mi2/NuRD) complex, MTA2, RbAp46, Mi2 and HDAC2, and recruits them to the proximal regions of the E-cadherin promoter for transcriptional repression. Depletion of these TWIST complex components from cancer cell lines that depend on TWIST for metastasis efficiently suppresses cell migration and invasion in culture and lung metastasis in mice. These findings not only provide novel mechanistic and functional links between TWIST and the Mi2/NuRD complex but also establish new essential roles for the components of Mi2/NuRD complex in cancer metastasis.
Fu
Junjiang
J
Department of Molecular and Cellular Biology, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA.
Qin
Li
L
He
Tao
T
Qin
Jun
J
Hong
Jun
J
Wong
Jiemin
J
Liao
Lan
L
Xu
Jianming
J
D000818:Animals; D001324:Autoantigens / Q000235:genetics / Q000378:metabolism; D015820:Cadherins / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D002465:Cell Movement; D058750:Epithelial-Mesenchymal Transition; D056464:Histone Deacetylase 2 / Q000378:metabolism; D006655:Histone Deacetylases / Q000235:genetics / Q000378:metabolism; D006801:Humans; D056245:Mi-2 Nucleosome Remodeling and Deacetylase Complex / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D051379:Mice; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D011401:Promoter Regions, Genetic; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism; D056524:Retinoblastoma-Binding Protein 7 / Q000378:metabolism; D051879:Twist-Related Protein 1 / Q000235:genetics / Q000378:metabolism / Q000502:physiology*
D001324:Autoantigens; C115323:CHD4 protein, human; D015820:Cadherins; C490746:RBBP7 protein, human; D034741:RNA, Small Interfering; D012097:Repressor Proteins; D056524:Retinoblastoma-Binding Protein 7; D051879:Twist-Related Protein 1; C120917:MTA2 protein, human; C533423:HDAC2 protein, human; D056464:Histone Deacetylase 2; D006655:Histone Deacetylases; D056245:Mi-2 Nucleosome Remodeling and Deacetylase Complex