Sperm-associated antigen 4, a novel hypoxia-inducible factor 1 target, regulates cytokinesis, and its expression correlates with the prognosis of renal cell carcinoma.

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 whose function was unknown. an HIF-1-specific target, is up-regulated in various cultured cells under hypoxia. Examination of expression using a tissue microarray consisting of 190 human renal cell carcinoma (RCC) samples revealed that duanyu1842G4 is an independent prognostic factor of cancer-specific mortality. Live-cell imaging revealed localization of duanyu1842G4 at the intercellular bridge in telophase. We also studied cells in which duanyu1842G4 was knocked down. Hypoxia enhances tetraploidy, which disturbs cell proliferation, and knockdown of duanyu1842G4 increased tetraploid formation and decreased cell proliferation under both normoxic and hypoxic conditions. Studies using deletion mutants of duanyu1842G4 also suggested the involvement of duanyu1842G4 in cytokinesis. Microarray analysis confirmed dysregulation of cytokinesis-related genes by knockdown of In conclusion, duanyu1842G4 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.

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