title: JARID1B Enables Transit between Distinct States of the Stem-like Cell Population in Oral Cancers.
abstract: The degree of heterogeneity among cancer stem cells (CSC) remains ill-defined and may hinder effective anti-CSC therapy. Evaluation of oral cancers for such heterogeneity identified two compartments within the CSC pool. One compartment was detected using a reporter for expression of the H3K4me3 demethylase JARID1B to isolate a JARID1B(high) fraction of cells with stem cell-like function. JARID1B(high) cells expressed oral CSC markers including CD44 and ALDH1 and showed increased PI3K pathway activation. They were distinguished from a fraction in a G0-like cell-cycle state characterized by low reactive oxygen species and suppressed PI3K/AKT signaling. G0-like cells lacked conventional CSC markers but were primed to acquire stem cell-like function by upregulating JARID1B, which directly mediated transition to a state expressing known oral CSC markers. The transition was regulated by PI3K signals acting upstream of JARID1B expression, resulting in PI3K inhibition depleting JARID1B(high) cells but expanding the G0-like subset. These findings define a novel developmental relationship between two cell phenotypes that may jointly contribute to CSC maintenance. Expansion of the G0-like subset during targeted depletion of JARID1B(high) cells implicates it as a candidate therapeutic target within the oral CSC pool. Cancer Res; 76(18); 5538-49. ©2016 AACR.
authors.affiliation: Department of Otorhinolaryngology, University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Nicole D
authors.initials: ND
authors.lastname: Facompre
authors.affiliation: Department of Otorhinolaryngology, University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Kayla M
authors.initials: KM
authors.lastname: Harmeyer
authors.affiliation: Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts.
authors.forename: Xavier
authors.initials: X
authors.lastname: Sole
authors.affiliation: Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts.
authors.forename: Sheheryar
authors.initials: S
authors.lastname: Kabraji
authors.affiliation: Department of Otorhinolaryngology, University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Zachary
authors.initials: Z
authors.lastname: Belden
authors.affiliation: Department of Otorhinolaryngology, University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Varun
authors.initials: V
authors.lastname: Sahu
authors.affiliation: Department of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Kelly
authors.initials: K
authors.lastname: Whelan
authors.affiliation: Department of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Koji
authors.initials: K
authors.lastname: Tanaka
authors.affiliation: Department of Otorhinolaryngology, University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Gregory S
authors.initials: GS
authors.lastname: Weinstein
authors.affiliation: Department of Pathology, University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Kathleen T
authors.initials: KT
authors.lastname: Montone
authors.affiliation: University Hospital, Essen, Germany.
authors.forename: Alexander
authors.initials: A
authors.lastname: Roesch
authors.affiliation: Department of Biostatistics, University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Phyllis A
authors.initials: PA
authors.lastname: Gimotty
authors.affiliation: The Wistar Institute, Philadelphia, Pennsylvania.
authors.forename: Meenhard
authors.initials: M
authors.lastname: Herlyn
authors.affiliation: Department of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Anil K
authors.initials: AK
authors.lastname: Rustgi
authors.affiliation: Department of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Nakagawa
authors.affiliation: Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts.
authors.forename: Sridhar
authors.initials: S
authors.lastname: Ramaswamy
authors.affiliation: Department of Otorhinolaryngology, University of Pennsylvania, Philadelphia, Pennsylvania. The Wistar Institute, Philadelphia, Pennsylvania. VA Medical Center, Philadelphia, Pennsylvania. devraj.basu@uphs.upenn.edu.
authors.forename: Devraj
authors.initials: D
authors.lastname: Basu
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002294:Carcinoma, Squamous Cell / Q000378:metabolism / Q000473:pathology*; D045744:Cell Line, Tumor; D002469:Cell Separation; D005434:Flow Cytometry; D006258:Head and Neck Neoplasms / Q000378:metabolism / Q000473:pathology*; D064593:Heterografts; D006801:Humans; D056484:Jumonji Domain-Containing Histone Demethylases / Q000378:metabolism*; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D018613:Microscopy, Confocal; D009062:Mouth Neoplasms / Q000378:metabolism / Q000473:pathology*; D014411:Neoplastic Stem Cells / Q000378:metabolism / Q000473:pathology*; D009687:Nuclear Proteins / Q000378:metabolism*; D016133:Polymerase Chain Reaction; D012097:Repressor Proteins / Q000378:metabolism*; D000077195:Squamous Cell Carcinoma of Head and Neck
chemical_list: D009687:Nuclear Proteins; D012097:Repressor Proteins; D056484:Jumonji Domain-Containing Histone Demethylases; C119611:KDM5B protein, human