Genistein inhibits prostate cancer cell growth by targeting miR-34a and oncogenic HOTAIR.
OBJECTIVE
Genistein is a soy isoflavone that has antitumor activity both in vitro and in vivo. It has been shown that genistein inhibits many type of cancers including prostate cancer (PCa) by regulating several cell signaling pathways and microRNAs (miRNAs). Recent studies suggest that the long non-coding RNAs (lncRNAs) are also involved in many cellular processes. At present there are no reports about the relationship between gensitein, miRNAs and lncRNAs. In this study, we focused on miRNAs, lncRNA that are regulated by genistein and investigated their functional role in PCa.


METHODS
Microarray (SurePrint G3 Human GE 8×60K) was used for expression profiling of genistein treated and control PCa cells (PC3 and DU145). Functional assay (cell proliferation, migration, invasion, apoptosis and cell cycle assays) were performed with the PCa cell lines, PC3 and DU145. Both in vitro and in vivo (nude mouse) models were used for growth assays. Luciferase reporter assays were used for binding of miR-34a to HOTAIR.


RESULTS
LncRNA profiling showed that HOTAIR was highly regulated by genistein and its expression was higher in castration-resistant PCa cell lines than in normal prostate cells. Knockdown (siRNA) of HOTAIR decreased PCa cell proliferation, migration and invasion and induced apoptosis and cell cycle arrest. miR-34a was also up-regulated by genistein and may directly target HOTAIR in both PC3 and DU145 PCa cells.


CONCLUSIONS
Our results indicated that genistein inhibited PCa cell growth through down-regulation of oncogenic HOTAIR that is also targeted by tumor suppressor miR-34a. These findings enhance understanding of how genistein regulates lncRNA HOTAIR and miR-34a in PCa.
Department of Urology, San Francisco Veterans Affairs Medical Center and University of California San Francisco, San Francisco, California, USA.
Takeshi
T
Chiyomaru
Soichiro
S
Yamamura
Shinichiro
S
Fukuhara
Hirofumi
H
Yoshino
Takashi
T
Kinoshita
Shahana
S
Majid
Sharanjot
S
Saini
Inik
I
Chang
Yuichiro
Y
Tanaka
Hideki
H
Enokida
Naohiko
N
Seki
Masayuki
M
Nakagawa
Rajvir
R
Dahiya
D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001483:Base Sequence; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D019833:Genistein / Q000494:pharmacology*; D006801:Humans; D008297:Male; D035683:MicroRNAs / Q000235:genetics*; D058990:Molecular Targeted Therapy; D009361:Neoplasm Invasiveness; D009857:Oncogenes / Q000235:genetics*; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000473:pathology*; D062085:RNA, Long Noncoding / Q000235:genetics*
D000970:Antineoplastic Agents; C561566:HOTAIR long untranslated RNA, human; C522425:MIRN34 microRNA, human; D035683:MicroRNAs; D062085:RNA, Long Noncoding; D019833:Genistein