title: Sperm-associated antigen 4, a novel hypoxia-inducible factor 1 target, regulates cytokinesis, and its expression correlates with the prognosis of renal cell carcinoma.
abstract: Hypoxia plays a crucial role in many pathophysiological conditions, including cancer biology, and hypoxia-inducible factor (HIF) regulates transcriptional responses under hypoxia. To elucidate the cellular responses to hypoxia, we performed chromatin immunoprecipitation with deep sequencing in combination with microarray analysis and identified HIF-1 targets. We focused on one of the novel targets, sperm-associated antigen 4 (SPAG4), whose function was unknown. SPAG4, an HIF-1-specific target, is up-regulated in various cultured cells under hypoxia. Examination of SPAG4 expression using a tissue microarray consisting of 190 human renal cell carcinoma (RCC) samples revealed that SPAG4 is an independent prognostic factor of cancer-specific mortality. Live-cell imaging revealed localization of SPAG4 at the intercellular bridge in telophase. We also studied cells in which SPAG4 was knocked down. Hypoxia enhances tetraploidy, which disturbs cell proliferation, and knockdown of SPAG4 increased tetraploid formation and decreased cell proliferation under both normoxic and hypoxic conditions. Studies using deletion mutants of SPAG4 also suggested the involvement of SPAG4 in cytokinesis. Microarray analysis confirmed dysregulation of cytokinesis-related genes by knockdown of SPAG4. In conclusion, SPAG4 is an independent prognostic factor in RCC and plays a crucial role in cytokinesis to defend against hypoxia-induced tetraploid formation. This defensive mechanism may promote survival of cancer cells under hypoxic conditions, thus leading to poor prognosis.
authors.affiliation: Division of Nephrology and Endocrinology, University of Tokyo, Tokyo, Japan.
authors.forename: Kumi
authors.initials: K
authors.lastname: Shoji
authors.forename: Takashi
authors.initials: T
authors.lastname: Murayama
authors.forename: Imari
authors.initials: I
authors.lastname: Mimura
authors.forename: Takehiko
authors.initials: T
authors.lastname: Wada
authors.forename: Haruki
authors.initials: H
authors.lastname: Kume
authors.forename: Akiteru
authors.initials: A
authors.lastname: Goto
authors.forename: Takamoto
authors.initials: T
authors.lastname: Ohse
authors.forename: Tetsuhiro
authors.initials: T
authors.lastname: Tanaka
authors.forename: Reiko
authors.initials: R
authors.lastname: Inagi
authors.forename: Frans A
authors.initials: FA
authors.lastname: van der Hoorn
authors.forename: Ichiro
authors.initials: I
authors.lastname: Manabe
authors.forename: Yukio
authors.initials: Y
authors.lastname: Homma
authors.forename: Masashi
authors.initials: M
authors.lastname: Fukayama
authors.forename: Takashi
authors.initials: T
authors.lastname: Sakurai
authors.forename: Takeshi
authors.initials: T
authors.lastname: Hasegawa
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Aburatani
authors.forename: Tatsuhiko
authors.initials: T
authors.lastname: Kodama
authors.forename: Masaomi
authors.initials: M
authors.lastname: Nangaku
mesh_terms: D000328:Adult; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D002292:Carcinoma, Renal Cell / Q000175:diagnosis* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D015687:Cell Hypoxia / Q000235:genetics / Q000502:physiology; D049109:Cell Proliferation; D002478:Cells, Cultured; D048749:Cytokinesis / Q000235:genetics / Q000502:physiology*; D005260:Female; D055785:Gene Knockdown Techniques; D061307:Human Umbilical Vein Endothelial Cells / Q000378:metabolism / Q000473:pathology; D006801:Humans; D051793:Hypoxia-Inducible Factor 1 / Q000378:metabolism; D053208:Kaplan-Meier Estimate; D007680:Kidney Neoplasms / Q000175:diagnosis* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D008297:Male; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D009367:Neoplasm Staging; D011379:Prognosis; D013692:Telophase; D057891:Tetraploidy
chemical_list: D014408:Biomarkers, Tumor; D002352:Carrier Proteins; D051793:Hypoxia-Inducible Factor 1; D009363:Neoplasm Proteins; C114799:SPAG4 protein, human