title: By moonlighting in the nucleus, villin regulates epithelial plasticity.
abstract: Villin is a tissue-specific, actin-binding protein involved in the assembly and maintenance of microvilli in polarized epithelial cells. Conversely, villin is also linked with the loss of epithelial polarity and gain of the mesenchymal phenotype in migrating, invasive cells. In this study, we describe for the first time how villin can switch between these disparate functions to change tissue architecture by moonlighting in the nucleus. Our study reveals that the moonlighting function of villin in the nucleus may play an important role in tissue homeostasis and disease. Villin accumulates in the nucleus during wound repair, and altering the cellular microenvironment by inducing hypoxia increases the nuclear accumulation of villin. Nuclear villin is also associated with mouse models of tumorigenesis, and a systematic analysis of a large cohort of colorectal cancer specimens confirmed the nuclear distribution of villin in a subset of tumors. Our study demonstrates that nuclear villin regulates epithelial-mesenchymal transition (EMT). Altering the nuclear localization of villin affects the expression and activity of Slug, a key transcriptional regulator of EMT. In addition, we find that villin directly interacts with a transcriptional corepressor and ligand of the Slug promoter, ZBRK1. The outcome of this study underscores the role of nuclear villin and its binding partner ZBRK1 in the regulation of EMT and as potential new therapeutic targets to inhibit tumorigenesis.
authors.affiliation: Department of Biology and Biochemistry, University of Houston, Houston, TX 77204.
authors.forename: Srinivas
authors.initials: S
authors.lastname: Patnaik
authors.affiliation: Department of Biology and Biochemistry, University of Houston, Houston, TX 77204.
authors.forename: Sudeep P
authors.initials: SP
authors.lastname: George
authors.affiliation: Department of Biology and Biochemistry, University of Houston, Houston, TX 77204.
authors.forename: Eric
authors.initials: E
authors.lastname: Pham
authors.affiliation: Department of Biology and Biochemistry, University of Houston, Houston, TX 77204.
authors.forename: Swati
authors.initials: S
authors.lastname: Roy
authors.affiliation: Department of Biology and Biochemistry, University of Houston, Houston, TX 77204.
authors.forename: Kanchan
authors.initials: K
authors.lastname: Singh
authors.affiliation: Olivia Newton-John Cancer Research Institute, La Trobe University School of Cancer Medicine, Melbourne, VIC 3084, Australia.
authors.forename: John M
authors.initials: JM
authors.lastname: Mariadason
authors.affiliation: Department of Biology and Biochemistry, University of Houston, Houston, TX 77204 Baylor College of Medicine, Houston, TX 77030 skhurana@uh.edu seema.khurana@bcm.edu.
authors.forename: Seema
authors.initials: S
authors.lastname: Khurana
mesh_terms: D021581:Active Transport, Cell Nucleus; D000818:Animals; D015179:Colorectal Neoplasms / Q000378:metabolism / Q000473:pathology; D004285:Dogs; D058750:Epithelial-Mesenchymal Transition; D015972:Gene Expression Regulation, Neoplastic; D006367:HeLa Cells; D006801:Humans; D061985:Madin Darby Canine Kidney Cells; D016513:Mice, SCID; D008840:Microfilament Proteins / Q000502:physiology*; D009368:Neoplasm Transplantation; D019913:Nuclear Localization Signals; D012097:Repressor Proteins / Q000378:metabolism*; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism
chemical_list: D008840:Microfilament Proteins; D019913:Nuclear Localization Signals; D012097:Repressor Proteins; C000604407:SNAI1 protein, human; C000604449:Snai2 protein, mouse; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors; C422407:ZNF350 protein, human; C026615:villin