Amino-terminal enhancer of split gene AES encodes a tumor and metastasis suppressor of prostate cancer.
A major cause of cancer death is its metastasis to the vital organs. Few effective therapies are available for metastatic castration-resistant prostate cancer (PCa), and progressive metastatic lesions such as lymph nodes and bones cause mortality. We recently identified AES as a metastasis suppressor for colon cancer. Here, we have studied the roles of AES in PCa progression. We analyzed the relationship between AES expression and PCa stages of progression by immunohistochemistry of human needle biopsy samples. We then performed overexpression and knockdown of AES in human PCa cell lines LNCaP, DU145 and PC3, and determined the effects on proliferation, invasion and metastasis in culture and in a xenograft model. We also compared the PCa phenotypes of Aes/Pten compound knockout mice with those of Pten simple knockout mice. Expression levels of AES were inversely correlated with clinical stages of human PCa. Exogenous expression of AES suppressed the growth of LNCaP cells, whereas the AES knockdown promoted it. We also found that AES suppressed transcriptional activities of androgen receptor and Notch signaling. Notably, AES overexpression in AR-defective DU145 and PC3 cells reduced invasion and metastasis to lymph nodes and bones without affecting proliferation in culture. Consistently, prostate epithelium-specific inactivation of Aes in Ptenflox/floxmice increased expression of Snail and MMP9, and accelerated growth, invasion and lymph node metastasis of the mouse prostate tumor. These results suggest that AES plays an important role in controlling tumor growth and metastasis of PCa by regulating both AR and Notch signaling pathways.
Department of Pharmacology, Kyoto University Graduate School of Medicine, Kyoto, Japan.|Department of Urology, Kyoto University Graduate School of Medicine, Kyoto, Japan.
Yoshiyuki
Y
Okada
Department of Pharmacology, Kyoto University Graduate School of Medicine, Kyoto, Japan.
Masahiro
M
Sonoshita
Department of Pharmacology, Kyoto University Graduate School of Medicine, Kyoto, Japan.
Fumihiko
F
Kakizaki
Department of Pharmacology, Kyoto University Graduate School of Medicine, Kyoto, Japan.
Naoki
N
Aoyama
Department of Pharmacology, Kyoto University Graduate School of Medicine, Kyoto, Japan.
Yoshiro
Y
Itatani
Department of Urology, Kyoto University Graduate School of Medicine, Kyoto, Japan.
Masayuki
M
Uegaki
Department of Urology, Kyoto University Graduate School of Medicine, Kyoto, Japan.
Hiromasa
H
Sakamoto
Department of Urology, Kyoto University Graduate School of Medicine, Kyoto, Japan.
Takashi
T
Kobayashi
Department of Urology, Kyoto University Graduate School of Medicine, Kyoto, Japan.
Takahiro
T
Inoue
Department of Urology, Kyoto University Graduate School of Medicine, Kyoto, Japan.
Tomomi
T
Kamba
Division of Cancer Genetics, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan.
Akira
A
Suzuki
Department of Urology, Kyoto University Graduate School of Medicine, Kyoto, Japan.
Osamu
O
Ogawa
Department of Pharmacology, Kyoto University Graduate School of Medicine, Kyoto, Japan.
M Mark
http://orcid.org/0000-0002-9032-4505
MM
Taketo
D000368:Aged; D000818:Animals; D015153:Blotting, Western; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics*; D056970:Co-Repressor Proteins; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D018345:Mice, Knockout; D008819:Mice, Nude; D016513:Mice, SCID; D008822:Mice, Transgenic; D009362:Neoplasm Metastasis; D051059:PTEN Phosphohydrolase / Q000235:genetics / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D011944:Receptors, Androgen / Q000235:genetics / Q000378:metabolism; D051880:Receptors, Notch / Q000235:genetics / Q000378:metabolism; D012097:Repressor Proteins / Q000235:genetics* / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000235:genetics; D014183:Transplantation, Heterologous; D025521:Tumor Suppressor Proteins / Q000235:genetics* / Q000378:metabolism
D056970:Co-Repressor Proteins; D011944:Receptors, Androgen; D051880:Receptors, Notch; D012097:Repressor Proteins; C498445:TLE5 protein, human; D025521:Tumor Suppressor Proteins; D051059:PTEN Phosphohydrolase
Androgen receptors; neoplasm invasiveness; neoplasm metastasis; prostatic neoplasms; transcription factors