Depletion of JARID1B induces cellular senescence in human colorectal cancer.
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.
Department of Frontier Science for Cancer and Chemotherapy, Osaka University, Graduate School of Medicine, Suita, Osaka 565-0871, Japan.
Katsuya
K
Ohta
Naotsugu
N
Haraguchi
Yoshihiro
Y
Kano
Yoshinori
Y
Kagawa
Masamitsu
M
Konno
Shimpei
S
Nishikawa
Atsushi
A
Hamabe
Shinichiro
S
Hasegawa
Hisataka
H
Ogawa
Takahito
T
Fukusumi
Mamoru
M
Uemura
Junichi
J
Nishimura
Taishi
T
Hata
Ichiro
I
Takemasa
Tsunekazu
T
Mizushima
Yuko
Y
Noguchi
Miyuki
M
Ozaki
Toshihiro
T
Kudo
Daisuke
D
Sakai
Taroh
T
Satoh
Miwa
M
Fukami
Masaru
M
Ishii
Hirofumi
H
Yamamoto
Yuichiro
Y
Doki
Masaki
M
Mori
Hideshi
H
Ishii
D000230:Adenocarcinoma / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D018951:Antigens, CD20 / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000378:metabolism; D016922:Cellular Senescence; D015179:Colorectal Neoplasms / Q000378:metabolism* / Q000473:pathology; D055785:Gene Knockdown Techniques; D006801:Humans; D056484:Jumonji Domain-Containing Histone Demethylases / Q000378:metabolism*; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009368:Neoplasm Transplantation; D014411:Neoplastic Stem Cells; D009687:Nuclear Proteins / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000235:genetics; D012097:Repressor Proteins / Q000378:metabolism*; D047368:Tumor Burden
D018951:Antigens, CD20; D009687:Nuclear Proteins; D034741:RNA, Small Interfering; D012097:Repressor Proteins; D056484:Jumonji Domain-Containing Histone Demethylases; C119611:KDM5B protein, human