Influence of small interfering RNA corresponding to ets homologous factor on senescence-associated modulation of prostate carcinogenesis

Authors:
Park C, Lee I, Kang WK
In:
Source: Mol Cancer Ther
Publication Date: (2006)
Issue: 5(12): 3191-6
Research Area:
Cancer Research/Cell Biology
Cells used in publication:
DU 145
Species: human
Tissue Origin: brain
MDA-MB-468
Species: human
Tissue Origin: breast
Platform:
Nucleofectorâ„¢ I/II/2b
Abstract
Senescence is thought to be an inherent tumor-suppressive mechanism. In the process of identifying senescence-associated genes, we found significant suppression of the ets homologous factor (EHF) in cancer cells in a state of DNA damage-induced senescence. In this study, we show that EHF provides substantial drug resistance in PC-3 prostate cancer cells by inhibiting senescence and cell cycle arrest. Knockdown of EHF by small interfering RNA inhibited cell proliferation and induced a premature cellular senescence characterized by hypophosphorylation of Rb and increased level of p27, with concomitant decreases of cyclin A, cdc2, and E2F1. Telomeric repeat amplification protocol analysis showed that transient EHF knockdown significantly decreased telomerase activity, whereas this activity was increased by overexpression of EHF. In vivo tumorigenesis analyses revealed that tumors derived from EHF knockdown cells were significantly smaller than those derived from control cells (P < 0.0001). Further, the preestablished tumors were reduced after the injection of small interfering RNA corresponding to EHF (P = 0.0122). Collectively, these observations indicate that aberrant expression of EHF and the subsequent disruption of p27-mediated senescence and telomerase activity is likely to contribute significantly to tumor progression, and furthermore that EHF might be a promising target for future cancer therapeutics.