Wwox suppresses prostate cancer cell growth through modulation of ErbB2-mediated androgen receptor signaling.
The expression of the WWOX tumor suppressor gene is lost or reduced in a large fraction of various cancers, including prostate cancer. We previously reported that Wwox overexpression induced apoptosis and suppressed prostate cancer growth in vitro and in vivo. In this study, pathways through which Wwox contributes to control of prostate cancer cell growth have been investigated. We found that Wwox interacts with Ap2gamma and prevents it from entering the nucleus to bind the ERBB2 promoter region to activate transcription of ERBB2, a mediator of androgen receptor activity and prostate cancer cell growth at limiting androgen concentration. Ectopic expression of Wwox reduced ErbB2 protein expression in vitro and expression of Wwox protein inversely correlated with expression of ErbB2 protein in prostate cancer tissues. Furthermore, Wwox suppressed Ap2gamma/ErbB2-induced prostate cancer cell growth and suppressed prostate-specific antigen secretion through interaction with Ap2gamma and down-modulation of ErbB2, an effect that required functional androgen receptor.
Qin
Haiyan R
HR
Department of Molecular Virology, Immunology and Medical Genetics, Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio 43210, USA.
Iliopoulos
Dimitrios
D
Nakamura
Tatsuya
T
Costinean
Stefan
S
Volinia
Stefano
S
Druck
Teresa
T
Sun
Jin
J
Okumura
Hiroshi
H
Huebner
Kay
K
D002455:Cell Division / Q000502:physiology*; D045744:Cell Line, Tumor; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008297:Male; D010088:Oxidoreductases / Q000502:physiology*; D011401:Promoter Regions, Genetic; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology; D034741:RNA, Small Interfering / Q000235:genetics; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics* / Q000378:metabolism; D011944:Receptors, Androgen / Q000235:genetics* / Q000502:physiology; D015398:Signal Transduction; D014158:Transcription, Genetic; D014162:Transfection; D025521:Tumor Suppressor Proteins / Q000502:physiology*; D000074584:WW Domain-Containing Oxidoreductase
D010088:Oxidoreductases; D034741:RNA, Small Interfering; D018719:Erb-b2 Receptor Tyrosine Kinases; D011944:Receptors, Androgen; D025521:Tumor Suppressor Proteins; D000074584:WW Domain-Containing Oxidoreductase; C486071:WWOX protein, human; C508053:ERBB2 protein, human