title: Identification of function for CD44 intracytoplasmic domain (CD44-ICD): modulation of matrix metalloproteinase 9 (MMP-9) transcription via novel promoter response element.
abstract: CD44 is a multifunctional cell receptor that conveys a cancer phenotype, regulates macrophage inflammatory gene expression and vascular gene activation in proatherogenic environments, and is also a marker of many cancer stem cells. CD44 undergoes sequential proteolytic cleavages that produce an intracytoplasmic domain called CD44-ICD. However, the role of CD44-ICD in cell function is unknown. We take a major step toward the elucidation of the CD44-ICD function by using a CD44-ICD-specific antibody, a modification of a ChIP assay to detect small molecules, and extensive computational analysis. We show that CD44-ICD translocates into the nucleus, where it then binds to a novel DNA consensus sequence in the promoter region of the MMP-9 gene to regulate its expression. We also show that the expression of many other genes that contain this novel response element in their promoters is up- or down-regulated by CD44-ICD. Furthermore, hypoxia-inducible factor-1α (Hif1α)-responsive genes also have the CD44-ICD consensus sequence and respond to CD44-ICD induction under normoxic conditions and therefore independent of Hif1α expression. Additionally, CD44-ICD early responsive genes encode for critical enzymes in the glycolytic pathway, revealing how CD44 could be a gatekeeper of the Warburg effect (aerobic glycolysis) in cancer cells and possibly cancer stem cells. The link of CD44 to metabolism is novel and opens a new area of research not previously considered, particularly in the study of obesity and cancer. In summary, our results finally give a function to the CD44-ICD and will accelerate the study of the regulation of many CD44-dependent genes.
authors.affiliation: Department of Obstetrics and Gynecology and Reproductive Sciences, Division of Gynecologic Oncology, University of Medicine and Dentistry of New Jersey/Robert Wood Johnson Medical School, New Brunswick, New Jersey 08901, USA.
authors.forename: Karl E
authors.initials: KE
authors.lastname: Miletti-González
authors.forename: Kyle
authors.initials: K
authors.lastname: Murphy
authors.forename: Muthu N
authors.initials: MN
authors.lastname: Kumaran
authors.forename: Abhilash K
authors.initials: AK
authors.lastname: Ravindranath
authors.forename: Roman P
authors.initials: RP
authors.lastname: Wernyj
authors.forename: Swayamjot
authors.initials: S
authors.lastname: Kaur
authors.forename: Gregory D
authors.initials: GD
authors.lastname: Miles
authors.forename: Elaine
authors.initials: E
authors.lastname: Lim
authors.forename: Rigel
authors.initials: R
authors.lastname: Chan
authors.forename: Marina
authors.initials: M
authors.lastname: Chekmareva
authors.forename: Debra S
authors.initials: DS
authors.lastname: Heller
authors.forename: David
authors.initials: D
authors.lastname: Foran
authors.forename: Wenjin
authors.initials: W
authors.lastname: Chen
authors.forename: Michael
authors.initials: M
authors.lastname: Reiss
authors.forename: Elisa V
authors.initials: EV
authors.lastname: Bandera
authors.forename: Kathleen
authors.initials: K
authors.lastname: Scotto
authors.forename: Lorna
authors.initials: L
authors.lastname: Rodríguez-Rodríguez
mesh_terms: D021581:Active Transport, Cell Nucleus; D002467:Cell Nucleus / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D005260:Female; D006019:Glycolysis / Q000235:genetics; D006801:Humans; D018960:Hyaluronan Receptors / Q000235:genetics / Q000378:metabolism*; D020780:Matrix Metalloproteinase 9 / Q000096:biosynthesis* / Q000235:genetics; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D014411:Neoplastic Stem Cells / Q000378:metabolism* / Q000473:pathology; D017434:Protein Structure, Tertiary; D020218:Response Elements; D014158:Transcription, Genetic
chemical_list: C497483:CD44 protein, human; D018960:Hyaluronan Receptors; D009363:Neoplasm Proteins; D020780:Matrix Metalloproteinase 9