Overexpression of the JmjC histone demethylase KDM5B in human carcinogenesis: involvement in the proliferation of cancer cells through the E2F/RB pathway

By S. Hayami, Masanori Yoshimatsu, A. Veerakumarasivam, M. Unoki, Yukiko Iwai, Tatsuhiko Tsunoda, Helen I. Field, John D. Kelly, David E. Neal, H. Yamaue and 3 more. 2010

222 citations recorded by the source corpus.

BackgroundAlthough an increasing number of histone demethylases have been identified and biochemically characterized, their biological functions largely remain uncharacterized, particularly in the context of human diseases such as cancer. We investigated the role of KDM5B, a JmjC histone demethylase, in human carcinogenesis. Quantitative RT-PCR and microarray analyses were used to examine the expression profiles of histone demethylases in clinical tissue samples. We also examined the functional effects of KDM5B on the growth of cancer cell lines treated with small interfering RNAs (siRNAs). Downstream genes and signal cascades induced by KDM5B expression were identified from Affymetrix Gene Chip experiments, and validated by real-time PCR and reporter assays. Cell cycle-dependent characteristics of KDM5B were identified by immunofluorescence and FACS.ResultsQuantitative RT-PCR analysis confirmed that expression levels of KDM5B are significantly higher in human bladder cancer tissues than in their corresponding non-neoplastic bladder tissues (P < 0.0001). The expression profile analysis of clinical tissues also revealed up-regulation of KDM5B in various kinds of malignancies. Transfection of KDM5B-specific siRNA into various bladder and lung cancer cell lines significantly suppressed the proliferation of cancer cells and increased the number of cells in sub-G1 phase. Microarray expression analysis indicated that E2F1 and E2F2 are downstream genes in the KDM5B pathway.ConclusionsInhibition of KDM5B may affect apoptosis and reduce growth of cancer cells. Further studies will explore the pan-cancer therapeutic potential of KDM5B inhibition.

Subfields: Molecular Biology

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Citations in the corpus

The Histone Demethylase JMJD2B Plays an Essential Role in Human Carcinogenesis through Positive Regulation of Cyclin-Dependent Kinase 6 (2011, methodology): “Coupled cell-cycle and cell proliferation assay A 50-bromo-20-deoxyuridine (BrdU) flow kit (BD Pharmingen) was used to determine the cell-cycle kinetics and to measure the incorporation of BrdU into DNA of proliferating cells (25, 26).”
PRMT6 increases cytoplasmic localization of p21CDKN1A in cancer cells through arginine methylation and makes more resistant to cytotoxic agents (2015, methodology): “Cell cycle analysis was conducted as previously described [46–50].”
RB1 methylation by SMYD2 enhances cell cycle progression through an increase of RB1 phosphorylation. (2012, methodology): “The siRNA sequences are described in Table W2. siRNA duplexes (final concentration, 100 nM) were transfected into bladder and lung cancer cell lines with Lipofectamine 2000 (Life Technologies, Carlsbad, CA) [17,22].”
SMYD2-dependent HSP90 methylation promotes cancer cell proliferation by regulating the chaperone complex formation. (2014, methodology): “293T cells were co-transfected with a FLAGSMYD2 expression vector and four different lengths of HA-HSP90AB1 vectors ([1–724], [1–500], [250–724] and [500–724]).”
PRMT1 promotes mitosis of cancer cells through arginine methylation of INCENP (2015, methodology): “siEGFP and siNegative control (siNC), which is a mixture of three different oligonucleotide duplexes were used as control siRNAs [16, 47-49].”
Late Cornified Envelope Group I, a Novel Target of p53, Regulates PRMT5 Activity (2014, background): “Current progress of molecular medicine revealed that the enzymes relevant to histonemethylation play critical roles in human carcinogenesis [28,35–45].”
Enhanced expression of EHMT2 is involved in the proliferation of cancer cells through negative regulation of SIAH1. (2011, methodology): “[26] Hayami S, Yoshimatsu M, Veerakumarasivam A, Unoki M, Iwai Y, Tsunoda T, Field HI, Kelly JD, Neal DE, Yamaue H, et al.”
SUV39H2 methylates and stabilizes LSD1 by inhibiting polyubiquitination in human cancer cells (2015, background): “Many reports have indicated that dysregulation of protein lysine methyltransferases and protein lysine demethylases has important roles in human tumorigenesis [32-37].”
The histone methyltransferase Wolf–Hirschhorn syndrome candidate 1‐like 1 (WHSC1L1) is involved in human carcinogenesis (2013, methodology): “The statistical procedure for micaroarray analysis was described preciously (Hayami et al., 2010, 2011; Cho et al., 2011a; Yoshimatsu et al., 2011).”
Histone lysine methyltransferase Wolf-Hirschhorn syndrome candidate 1 is involved in human carcinogenesis through regulation of the Wnt pathway. (2011, background): “[31] Hayami S, Yoshimatsu M, Veerakumarasivam A, Unoki M, Iwai Y, Tsunoda T, Field HI, Kelly JD, Neal DE, Yamaue H, et al.”
Dysregulation of AKT Pathway by SMYD2-Mediated Lysine Methylation on PTEN (2015, methodology): “siEnhanced green fluorescent protein and siNegative control (siNC), which is a mixture of three different oligonucleotide duplexes, were used as control siRNAs [25–28].”