Targeted knockdown of SEPT9-v1 inhibits tumor growth and angiogenesis of human prostate cancer cells concomitant with disruption of hypoxia-inducible factor-1 pathway

Abstract

Hypoxia-inducible factor-1 (HIF-1) is a key transcription factor in the hypoxic response pathway.We recently identified a novel interaction between HIF-1α 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-1α 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-1α 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-1α knockout colon cancer cells. In vivo, SEPT9-i1 depletion reduced HIF-1α 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. ©2010 AACR.