Depletion of JARID1B induces cellular senescence in human colorectal cancer

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.

SKP2 inactivation suppresses prostate tumorigenesis by mediating JARID1B ubiquitination

“…SKP2 deficiency induces cellular senescence in contexts of oncogenic insults [8], and recently JARID1B is associated with cellular senescence in colorectal cancer and retinoblastoma cells [38, 39]. We reasoned that K63-linked ubiquitination of JARID1B accumulated in nucleolus may contribute to SKP2-deficient induced cellular senescence.…”

Nitric Oxide Modifies Global Histone Methylation by Inhibiting Jumonji C Domain-containing Demethylases

“…Conversely, others have demonstrated that KDM6B acts as a tumor suppressor by regulating p53 nuclear stabilization (71). In colorectal cancer, depletion of KDM5B induced cellular senescence (72). In breast cancer, the methyltransferase G9a plays a critical role in the epigenetic regulation of epithelial-mesenchymal transition (73).…”

Immunohistochemical detection and clinicopathological significance of JARID1B/KDM5B and P16 expression in invasive ductal carcinoma of the breast

“…Ohta et al (2013) demonstrated that JARID1B/KDM5B may play a role in active chromatin compaction of the p16 promoter, contributing to gene silencing. Therefore, JA-RID1B/KDM5B depletion may lead to p16 activation.…”