title: Lysyl oxidase is induced by cell density-mediated cell cycle suppression via RB-E2F1-HIF-1α axis.
abstract: Remodeling of the matrix surrounding tumor cells plays a crucial role in the development and maintenance of cancer. Lysyl oxidase (LOX), a matrix remodeling factor, is induced by HIF-1α under hypoxic conditions and associated with tumor growth and metastasis. Here, we report that high cell density induces HIF-1α expression under normoxic condition, resulting in the promotion of LOX expression. This phenomenon was observed in the retinoblastoma tumor suppressor (RB)-proficient breast cancer cells but not in RB-deficient cells. In RB-proficient cancer cells, the cell cycle regulator E2F1 was down-regulated and cell cycle progression was inhibited at high density culture condition. Knockdown of E2F1 stabilized HIF-1α and promoted LOX expression, while knockdown of both E2F1 and HIF-1α prevented the up-regulation of LOX. These findings suggest that elevated cell density enhances cell cycle arrest and matrix remodeling via RB-E2F1-HIF-1α axis.
authors.affiliation: Division of Gene Regulation, Institute for Advanced Medical Research, School of Medicine, Keio University, Tokyo 160-8582, Japan.
authors.forename: Takaaki M
authors.initials: TM
authors.lastname: Goto
authors.forename: Yoshimi
authors.initials: Y
authors.lastname: Arima
authors.forename: Osamu
authors.initials: O
authors.lastname: Nagano
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Saya
mesh_terms: D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism; D002452:Cell Count; D059447:Cell Cycle Checkpoints / Q000235:genetics / Q000502:physiology; D002455:Cell Division; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic; D050687:E2F1 Transcription Factor / Q000235:genetics / Q000378:metabolism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D008249:Protein-Lysine 6-Oxidase / Q000235:genetics / Q000378:metabolism
chemical_list: D050687:E2F1 Transcription Factor; C493753:E2F1 protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D008249:Protein-Lysine 6-Oxidase