Tip60 promotes prostate cancer cell proliferation by translocation of androgen receptor into the nucleus.
BACKGROUND
There are currently few effective therapies for castration-resistant prostate cancer (CRPCa). CRPC which is resistant to castration is thought to result from increased activation of the androgen/androgen receptor (AR) signaling pathway, which may be augmented by AR coactivators.


METHODS
Luciferase reporter assay, Western blotting, quantitative real-time polymerase chain reaction, fluorescence microscopy, cell proliferation assay, and flow cytometry for cell-cycle analysis were used to resolve a role of Tip60 regulating AR in PCa cells.


RESULTS
Tip60 regulated transcriptions of AR target genes androgen independently. Tip60 knockdown induced translocation of AR into the cytoplasm. Acetylation-mimicking mutations in the nuclear localization signal sequence caused AR protein to mainly localize in the nucleus despite androgen starvation, whereas non-acetylation-mimicking mutations caused AR to mainly localize in the cytoplasm despite androgen stimulation. Tip60 overexpression in castration-resistant LNCaP derivative CxR cells resulted in increases in the acetylated form of AR and AR localization in the nucleus even without androgen. Consequently, Tip60 silencing suppressed the growth of AR-expressing PCa cells by inducing cell-cycle arrest at the G1 phase, similar to inhibition of androgen/AR signaling. Furthermore, Tip60 knockdown suppressed the cell growth of CxR cells.


CONCLUSIONS
Tip60 is involved in the proliferation of PCa cells as an AR coactivator. Modulation of Tip60 expression or function may be a useful strategy for developing novel therapeutics for PCa, even CRPC, which remain dependent on AR signaling, by overexpressing AR and its coactivators.
Shiota
Masaki
M
Department of Urology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
Yokomizo
Akira
A
Masubuchi
Daisuke
D
Tada
Yasuhiro
Y
Inokuchi
Junichi
J
Eto
Masatoshi
M
Uchiumi
Takeshi
T
Fujimoto
Naohiro
N
Naito
Seiji
S
D021581:Active Transport, Cell Nucleus; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism*; D049109:Cell Proliferation; D051548:Histone Acetyltransferases / Q000502:physiology*; D006801:Humans; D000074443:Lysine Acetyltransferase 5; D008297:Male; D011471:Prostatic Neoplasms / Q000473:pathology*; D021381:Protein Transport; D011944:Receptors, Androgen / Q000737:chemistry / Q000378:metabolism*; D014158:Transcription, Genetic
C410798:AR protein, human; D011944:Receptors, Androgen; D051548:Histone Acetyltransferases; C098489:KAT5 protein, human; D000074443:Lysine Acetyltransferase 5