Abstract

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.

Highlights

  • Rad9, a cell cycle checkpoint and DNA repair protein, is functionally related to human prostate tumorigenesis

  • This is primarily on the basis of two findings: 1) Rad9 knockdown results in decreased cell proliferation and increased apoptosis; and 2) Rad9 downregulation impairs in vitro migration and invasion of DU145 and PC3 cells and anchorage-independent growth of DU145 cells and renders DU145 and LNCaP cells more sensitive to anoikis, whereas restoration of Rad9 expression results in increased cell motility, invasion, anchorage-independent growth, and anoikis resistance

  • We investigated mechanistic details of the observed phenotypes and discovered that silencing of Rad9 leads to a marked down-regulation of integrin ␤1

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Summary

Introduction

A cell cycle checkpoint and DNA repair protein, is functionally related to human prostate tumorigenesis. Results: Rad deletion in prostate cancer cells impairs migration and invasion, sensitizes to anoikis, and down-regulates integrin ␤1. Transient or stable down-regulation of Rad impairs migration and invasion of the cells. Stable reduction of Rad renders DU145 cell growth anchorage-dependent. It decreases expression of integrin ␤1 protein and sensitizes DU145 and LNCaP cells to anoikis and impairs Akt activation. Stable expression of Mrad, the mouse homolog, in DU145/shRNA Rad cells restores migration, invasion, anchorage-independent growth, integrin ␤1 expression, and anoikis resistance with a concomitant elevation of Akt activation. We demonstrate for the first time that Rad contributes to prostate tumorigenesis by increasing tumor proliferation and survival and tumor migration and invasion, anoikis resistance, and anchorage-independent growth

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