TY - JOUR
T1 - Depletion of JARID1B induces cellular senescence in human colorectal cancer
AU - Ohta, Katsuya
AU - Haraguchi, Naotsugu
AU - Kano, Yoshihiro
AU - Kagawa, Yoshinori
AU - Konno, Masamitsu
AU - Nishikawa, Shimpei
AU - Hamabe, Atsushi
AU - Hasegawa, Shinichiro
AU - Ogawa, Hisataka
AU - Fukusumi, Takahito
AU - Uemura, Mamoru
AU - Nishimura, Junichi
AU - Hata, Taishi
AU - Takemasa, Ichiro
AU - Mizushima, Tsunekazu
AU - Noguchi, Yuko
AU - Ozaki, Miyuki
AU - Kudo, Toshihiro
AU - Sakai, Daisuke
AU - Satoh, Taroh
AU - Fukami, Miwa
AU - Ishii, Masaru
AU - Yamamoto, Hirofumi
AU - Doki, Yuichiro
AU - Mori, Masaki
AU - Ishii, Hideshi
PY - 2013/4
Y1 - 2013/4
N2 - The global incidence of colorectal cancer (CRC) is increasing. Although there are emerging epigenetic factors that contribute to the occurrence, development and metastasis of CRC, the biological significance of epigenetic molecular regulation in different subpopulations such as cancer stem cells remains to be elucidated. In this study, we investigated the functional roles of the H3K4 demethylase, jumonji, AT rich interactive domain 1B (JARID1B), an epigenetic factor required for the continuous cell growth of melanomas, in CRC. We found that CD44+/aldehyde dehydrogenase (ALDH)+ slowly proliferating immature CRC stem cell populations expressed relatively low levels of JARID1B and the differentiation marker, CD20, as well as relatively high levels of the tumor suppressor, p16.INK4A. Of note, lentiviral-mediated continuous JARID1B depletion resulted in the loss of epithelial differentiation and suppressed CRC cell growth, which was associated with the induction of phosphorylation by the c-Jun N-terminal kinase (Jnk.Sapk) and senescence-associated β-galactosidase activity. Moreover, green fluorescent-labeled cell tracking indicated that JARID1B-positive CRC cells had greater tumorigenicity than JARID1B-negative CRC cells after their subcutaneous inoculation into immunodeficient mice, although JARID1B-negative CRC cells resumed normal growth after a month, suggesting that continuous JARID1B inhibition is necessary for tumor eradication. Thus, JARID1B plays a role in CRC maintenance. JARID1B may be a novel molecular target for therapy-resistant cancer cells by the induction of cellular senescence.
AB - The global incidence of colorectal cancer (CRC) is increasing. Although there are emerging epigenetic factors that contribute to the occurrence, development and metastasis of CRC, the biological significance of epigenetic molecular regulation in different subpopulations such as cancer stem cells remains to be elucidated. In this study, we investigated the functional roles of the H3K4 demethylase, jumonji, AT rich interactive domain 1B (JARID1B), an epigenetic factor required for the continuous cell growth of melanomas, in CRC. We found that CD44+/aldehyde dehydrogenase (ALDH)+ slowly proliferating immature CRC stem cell populations expressed relatively low levels of JARID1B and the differentiation marker, CD20, as well as relatively high levels of the tumor suppressor, p16.INK4A. Of note, lentiviral-mediated continuous JARID1B depletion resulted in the loss of epithelial differentiation and suppressed CRC cell growth, which was associated with the induction of phosphorylation by the c-Jun N-terminal kinase (Jnk.Sapk) and senescence-associated β-galactosidase activity. Moreover, green fluorescent-labeled cell tracking indicated that JARID1B-positive CRC cells had greater tumorigenicity than JARID1B-negative CRC cells after their subcutaneous inoculation into immunodeficient mice, although JARID1B-negative CRC cells resumed normal growth after a month, suggesting that continuous JARID1B inhibition is necessary for tumor eradication. Thus, JARID1B plays a role in CRC maintenance. JARID1B may be a novel molecular target for therapy-resistant cancer cells by the induction of cellular senescence.
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U2 - 10.3892/ijo.2013.1799
DO - 10.3892/ijo.2013.1799
M3 - Article
C2 - 23354547
AN - SCOPUS:84874615877
VL - 42
SP - 1212
EP - 1218
JO - International Journal of Oncology
JF - International Journal of Oncology
SN - 1019-6439
IS - 4
ER -