Targeted knockdown of EGR-1 inhibits IL-8 production and IL-8-mediated invasion of prostate cancer cells through suppressing EGR-1/NF-kappaB synergy.
IL-8 produced by prostate cancer cells may be responsible for the androgen-independent growth of advanced prostate cancers. Accumulating evidence from microarray analyses and animal genetic models highlights the central involvement of the transcription factor early growth response-1 (EGR-1) in prostate carcinoma progression. It is unknown, however, whether knockdown of EGR-1 inhibits IL-8 production and IL-8-mediated tumor metastasis. Here we show that EGR-1 knockdown by a specific shRNA-Egr1 inhibited gene transcription and production of IL-8 by the human prostate cancer cell line DU145. Conversely, enforced expression of EGR-1 in EGR-1-lacking PC3 prostate cancer cells markedly enhanced IL-8 transcription and secretion. By using wild type and a series of mutant IL-8 promoter luciferase constructs, we found that the NF-kappaB binding site is important for EGR-1 regulation of IL-8. Furthermore, silencing EGR-1 suppressed a synergistically functional interaction between EGR-1 and NF-kappaB. Consequently, knockdown of EGR-1 inhibited IL-8-mediated tumor colony formation and invasion. Thus, targeted knockdown of EGR-1 could be an effective therapeutic approach against prostate cancer.
Ma
Jiajia
J
Hefei National Laboratory for Physical Sciences at Microscale and School of Life Sciences, University of Science and Technology of China, Hefei, Anhui 230027, China.
Ren
Zijia
Z
Ma
Yang
Y
Xu
Lu
L
Zhao
Ying
Y
Zheng
Chaogu
C
Fang
Yinghui
Y
Xue
Ting
T
Sun
Baolin
B
Xiao
Weihua
W
D000818:Animals; D045744:Cell Line, Tumor; D051766:Early Growth Response Protein 1 / Q000235:genetics / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D055785:Gene Knockdown Techniques; D015316:Genetic Therapy / Q000379:methods; D006801:Humans; D016209:Interleukin-8 / Q000235:genetics / Q000378:metabolism*; D008297:Male; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D009361:Neoplasm Invasiveness; D011401:Promoter Regions, Genetic; D011471:Prostatic Neoplasms / Q000378:metabolism / Q000473:pathology* / Q000628:therapy
C497325:EGR1 protein, human; D051766:Early Growth Response Protein 1; D016209:Interleukin-8; D016328:NF-kappa B