title: The histone H3K9 demethylase KDM3A promotes anoikis by transcriptionally activating pro-apoptotic genes BNIP3 and BNIP3L.
abstract: Epithelial cells that lose attachment to the extracellular matrix undergo a specialized form of apoptosis called anoikis. Here, using large-scale RNA interference (RNAi) screening, we find that KDM3A, a histone H3 lysine 9 (H3K9) mono- and di-demethylase, plays a pivotal role in anoikis induction. In attached breast epithelial cells, KDM3A expression is maintained at low levels by integrin signaling. Following detachment, integrin signaling is decreased resulting in increased KDM3A expression. RNAi-mediated knockdown of KDM3A substantially reduces apoptosis following detachment and, conversely, ectopic expression of KDM3A induces cell death in attached cells. We find that KDM3A promotes anoikis through transcriptional activation of BNIP3 and BNIP3L, which encode pro-apoptotic proteins. Using mouse models of breast cancer metastasis we show that knockdown of Kdm3a enhances metastatic potential. Finally, we find defective KDM3A expression in human breast cancer cell lines and tumors. Collectively, our results reveal a novel transcriptional regulatory program that mediates anoikis.
authors.affiliation: Department of Molecular, Cell and Cancer Biology, University of Massachusetts Medical School, Worcester, United States.|Howard Hughes Medical Institute, University of Massachusetts Medical School, Worcester, United States.
authors.forename: Victoria E
authors.initials: VE
authors.lastname: Pedanou
authors.affiliation: Department of Molecular Medicine, Université Laval, Quebec City, Canada.|Centre de recherche du CHU de Québec, CHUL, Québec PQ, Canada.
authors.forename: Stéphane
authors.initials: S
authors.lastname: Gobeil
authors.affiliation: Department of Medicine, Goodman Cancer Research Centre, McGill University, Montreal, Canada.
authors.forename: Sébastien
authors.initials: S
authors.lastname: Tabariès
authors.affiliation: Department of Molecular, Cell and Cancer Biology, University of Massachusetts Medical School, Worcester, United States.|Howard Hughes Medical Institute, University of Massachusetts Medical School, Worcester, United States.
authors.forename: Tessa M
authors.initials: TM
authors.lastname: Simone
authors.affiliation: Department of Molecular, Cell and Cancer Biology, University of Massachusetts Medical School, Worcester, United States.|Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, United States.|Program in Bioinformatics and Integrative Biology, University of Massachusetts Medical School, Worcester, United States.
authors.forename: Lihua Julie
authors.initials: LJ
authors.lastname: Zhu
authors.affiliation: Department of Medicine, Goodman Cancer Research Centre, McGill University, Montreal, Canada.
authors.forename: Peter M
authors.initials: PM
authors.lastname: Siegel
authors.affiliation: Department of Molecular, Cell and Cancer Biology, University of Massachusetts Medical School, Worcester, United States.|Howard Hughes Medical Institute, University of Massachusetts Medical School, Worcester, United States.
authors.forename: Michael R
authors.identifier: 0000-0003-3017-3298
authors.initials: MR
authors.lastname: Green
mesh_terms: D000818:Animals; D023102:Anoikis; D001943:Breast Neoplasms / Q000473:pathology / Q000556:secondary; D002448:Cell Adhesion; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D004847:Epithelial Cells / Q000502:physiology*; D005820:Genetic Testing; D006801:Humans; D056484:Jumonji Domain-Containing Histone Demethylases / Q000378:metabolism*; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D034622:RNA Interference; D014158:Transcription, Genetic; D025521:Tumor Suppressor Proteins / Q000378:metabolism*
chemical_list: C090121:BNIP3 protein, human; C116838:BNIP3L protein, human; D008565:Membrane Proteins; D011518:Proto-Oncogene Proteins; D025521:Tumor Suppressor Proteins; D056484:Jumonji Domain-Containing Histone Demethylases; C530247:KDM3A protein, human
keywords: BNIP3; BNIP3L; KDM3A; anoikis; cell biology; chromosomes; genes; histone demethylase; human; mouse