Targeted knockdown of SEPT9_v1 inhibits tumor growth and angiogenesis of human prostate cancer cells concomitant with disruption of hypoxia-inducible factor-1 pathway.
Hypoxia-inducible factor-1 (HIF-1) is a key transcription factor in the hypoxic response pathway. We recently identified a novel interaction between HIF-1alpha and the mammalian septin family member, septin 9 protein, isoform 1 (SEPT9_i1), a protein product of septin 9 transcript variant 1 (SEPT9_v1). Septins are a highly conserved family of GTP-binding cytoskeletal proteins that are implicated in multiple cellular functions, including oncogenesis. SEPT9_i1 binds and stabilizes HIF-1alpha protein and stimulates HIF-1 transcriptional activity by preventing its RACK1-mediated ubiquitination and degradation. SEPT9_i1-HIF-1 activation promotes tumor growth and angiogenesis. The effect of SEPT9_v1 silencing in prostate cancer cells was studied. SEPT9_v1 stable knockdown was generated in PC-3 cells using a specific shRNA. SEPT9_v1 silencing reduced HIF-1alpha protein expression and inhibited HIF-1 transcriptional activity. SEPT9_v1 knockdown affected cell morphology, deregulated cell cycle, and decreased migration. The antiproliferative effect of shSEPT9_v1 was abolished in HIF-1alpha knockout colon cancer cells. In vivo, SEPT9_i1 depletion reduced HIF-1alpha protein expression, cellular proliferation, tumor growth, and angiogenesis. These results provide new insights and validation for applying SEPT9_v1 as a potential target for antitumor therapy by interrupting the HIF-1 pathway.
Amir
Sharon
S
Prostate Cancer Research Laboratory, Department of Urology, Tel Aviv Sourasky Medical Center, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
Golan
Maya
M
Mabjeesh
Nicola J
NJ
D002453:Cell Cycle / Q000235:genetics; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics; D049109:Cell Proliferation; D048430:Cell Shape / Q000235:genetics; D003598:Cytoskeletal Proteins / Q000172:deficiency / Q000235:genetics*; D015536:Down-Regulation / Q000235:genetics; D019204:GTP-Binding Proteins / Q000172:deficiency / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics; D020868:Gene Silencing / Q000502:physiology; D006131:Growth Inhibitors / Q000172:deficiency / Q000235:genetics*; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism* / Q000502:physiology; D008297:Male; D009389:Neovascularization, Pathologic / Q000235:genetics / Q000378:metabolism* / Q000517:prevention & control*; D011471:Prostatic Neoplasms / Q000098:blood supply / Q000235:genetics* / Q000473:pathology / Q000517:prevention & control*; D034622:RNA Interference; D058112:Septins; D015398:Signal Transduction / Q000235:genetics*
D003598:Cytoskeletal Proteins; D006131:Growth Inhibitors; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D019204:GTP-Binding Proteins; C474315:SEPTIN9 protein, human; D058112:Septins