Depletion of JARID1B induces cellular senescence in human colorectal cancer

Katsuya Ohta, Naotsugu Haraguchi, Yoshihiro Kano, Yoshinori Kagawa, Masamitsu Konno, Shimpei Nishikawa, Atsushi Hamabe, Shinichiro Hasegawa, Hisataka Ogawa, Takahito Fukusumi, Mamoru Uemura, Junichi Nishimura, Taishi Hata, Ichiro Takemasa, Tsunekazu Mizushima, Yuko Noguchi, Miyuki Ozaki, Toshihiro Kudo, Daisuke Sakai, Taroh SatohMiwa Fukami, Masaru Ishii, Hirofumi Yamamoto, Yuichiro Doki, Masaki Mori, Hideshi Ishii

Research output: Contribution to journalArticlepeer-review

37 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)1212-1218
Number of pages7
JournalInternational journal of oncology
Volume42
Issue number4
DOIs
Publication statusPublished - Apr 2013

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

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