Rad9 protein contributes to prostate tumor progression by promoting cell migration and anoikis resistance.
Rad9 as part of the Rad9-Hus1-Rad1 complex is known to participate in cell cycle checkpoint activation and DNA repair. However, Rad9 can act as a sequence-specific transcription factor, modulating expression of a number of genes. Importantly, Rad9 is up-regulated in prostate cancer cell lines and clinical specimens. Its expression correlates positively with advanced stage tumors and its down-regulation reduces tumor burden in mice. We show here that transient down-regulation of Rad9 by RNA interference reduces DU145 and PC3 prostate cancer cell proliferation and survival in vitro. In addition, transient or stable down-regulation of Rad9 impairs migration and invasion of the cells. Moreover, stable reduction of Rad9 renders DU145 cell growth anchorage-dependent. It also decreases expression of integrin β1 protein and sensitizes DU145 and LNCaP cells to anoikis and impairs Akt activation. On the other hand, stable expression of Mrad9, the mouse homolog, in DU145/shRNA Rad9 cells restores migration, invasion, anchorage-independent growth, integrin β1 expression, and anoikis resistance with a concomitant elevation of Akt activation. We thus demonstrate for the first time that Rad9 contributes to prostate tumorigenesis by increasing not only tumor proliferation and survival but also tumor migration and invasion, anoikis resistance, and anchorage-independent growth.
Center for Radiological Research, Columbia University College of Physicians and Surgeons, New York, New York 10032, USA.
Constantinos G
CG
Broustas
Aiping
A
Zhu
Howard B
HB
Lieberman
D023102:Anoikis; D002448:Cell Adhesion; D002453:Cell Cycle; D018797:Cell Cycle Proteins / Q000378:metabolism*; D045744:Cell Line, Tumor; D002465:Cell Movement; D004260:DNA Repair; D018450:Disease Progression; D015536:Down-Regulation; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing; D006801:Humans; D019012:Integrin beta1 / Q000096:biosynthesis; D008297:Male; D009361:Neoplasm Invasiveness; D011471:Prostatic Neoplasms / Q000378:metabolism / Q000473:pathology*; D034622:RNA Interference; D015398:Signal Transduction
D018797:Cell Cycle Proteins; D019012:Integrin beta1; C069930:rad9 protein