Influence of small interfering RNA corresponding to ets homologous factor on senescence-associated modulation of prostate carcinogenesis.
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.
Park
Chaehwa
C
Cancer Center, Samsung Medical Center, Sungkyunkwan University School of Medicine, 50 Irwon-Dong, Seoul 135-710, Korea. cpark@smc.samsung.co.kr
Lee
Inkyoung
I
Kang
Won Ki
WK
D000818:Animals; D002453:Cell Cycle / Q000235:genetics; D045744:Cell Line, Tumor; D016922:Cellular Senescence / Q000235:genetics; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000096:biosynthesis / Q000235:genetics; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000096:biosynthesis / Q000235:genetics; D004249:DNA Damage; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology / Q000628:therapy; D034741:RNA, Small Interfering / Q000235:genetics*; D019098:Telomerase / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000037:antagonists & inhibitors / Q000235:genetics*; D014162:Transfection
D019941:Cyclin-Dependent Kinase Inhibitor p16; C403306:EHF protein, human; D034741:RNA, Small Interfering; D014157:Transcription Factors; D050760:Cyclin-Dependent Kinase Inhibitor p27; D019098:Telomerase