title: Targeting of the tumor suppressor GRHL3 by a miR-21-dependent proto-oncogenic network results in PTEN loss and tumorigenesis.
abstract: Despite its prevalence, the molecular basis of squamous cell carcinoma (SCC) remains poorly understood. Here, we identify the developmental transcription factor Grhl3 as a potent tumor suppressor of SCC in mice, and demonstrate that targeting of Grhl3 by a miR-21-dependent proto-oncogenic network underpins SCC in humans. Deletion of Grhl3 in adult epidermis evokes loss of expression of PTEN, a direct GRHL3 target, resulting in aggressive SCC induced by activation of PI3K/AKT/mTOR signaling. Restoration of Pten expression completely abrogates SCC formation. Reduced levels of GRHL3 and PTEN are evident in human skin, and head and neck SCC, associated with increased expression of miR-21, which targets both tumor suppressors. Our data define the GRHL3-PTEN axis as a critical tumor suppressor pathway in SCC.
authors.affiliation: Department of Medicine, Monash University Central Clinical School, Prahran, Victoria 3181, Australia.
authors.forename: Charbel
authors.initials: C
authors.lastname: Darido
authors.forename: Smitha R
authors.initials: SR
authors.lastname: Georgy
authors.forename: Tomasz
authors.initials: T
authors.lastname: Wilanowski
authors.forename: Sebastian
authors.initials: S
authors.lastname: Dworkin
authors.forename: Alana
authors.initials: A
authors.lastname: Auden
authors.forename: Quan
authors.initials: Q
authors.lastname: Zhao
authors.forename: Gerhard
authors.initials: G
authors.lastname: Rank
authors.forename: Seema
authors.initials: S
authors.lastname: Srivastava
authors.forename: Moira J
authors.initials: MJ
authors.lastname: Finlay
authors.forename: Anthony T
authors.initials: AT
authors.lastname: Papenfuss
authors.forename: Pier Paolo
authors.initials: PP
authors.lastname: Pandolfi
authors.forename: Richard B
authors.initials: RB
authors.lastname: Pearson
authors.forename: Stephen M
authors.initials: SM
authors.lastname: Jane
mesh_terms: D000818:Animals; D001483:Base Sequence; D002294:Carcinoma, Squamous Cell / Q000139:chemically induced / Q000235:genetics*; D002454:Cell Differentiation / Q000235:genetics; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D017353:Gene Deletion; D015972:Gene Expression Regulation, Neoplastic; D020022:Genetic Predisposition to Disease; D006706:Homeostasis; D015603:Keratinocytes / Q000473:pathology; D051379:Mice; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D008969:Molecular Sequence Data; D051059:PTEN Phosphohydrolase / Q000235:genetics*; D016415:Sequence Alignment; D012878:Skin Neoplasms / Q000139:chemically induced / Q000235:genetics*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*
chemical_list: D004268:DNA-Binding Proteins; C499942:Grhl3 protein, mouse; C531950:MIRN21 microRNA, mouse; D035683:MicroRNAs; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; D051059:PTEN Phosphohydrolase; C487757:Pten protein, mouse