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. 2011 Mar 1;3(1):1383-404.
doi: 10.3390/cancers3011383.

Epigenetic Regulation by Lysine Demethylase 5 (KDM5) Enzymes in Cancer

Lauren P Blair  1 , Jian Cao, Mike Ran Zou, Joyce Sayegh, Qin Yan
Affiliations

Epigenetic Regulation by Lysine Demethylase 5 (KDM5) Enzymes in Cancer

Lauren P Blair et al. Cancers (Basel). .

Abstract

Similar to genetic alterations, epigenetic aberrations contribute significantly to tumor initiation and progression. In many cases, these changes are caused by activation or inactivation of the regulators that maintain epigenetic states. Here we review our current knowledge on the KDM5/JARID1 family of histone demethylases. This family of enzymes contains a JmjC domain and is capable of removing tri- and di- methyl marks from lysine 4 on histone H3. Among these proteins, RBP2 mediates drug resistance while JARID1B is required for melanoma maintenance. Preclinical studies suggest inhibition of these enzymes can suppress tumorigenesis and provide strong rationale for development of their inhibitors for use in cancer therapy.

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Figures

Figure 1.
Figure 1.
Domain structure of JARID1 proteins from Drosophila and humans.
Figure 2.
Figure 2.
(A) The demethylase capabilities of Lid can contribute to gene repression by removing H3K4me3 marks, which are associated with active genes [73-75]. (B) Binding of dMyc to Lid inactivates its demethylase activity but retains H3K4me3 binding ability, allowing it to recruit dMyc to actively transcribed genes [76,77]. (C) Lid represses Notch target genes by associating with the LAF complex and demethylating H3K4me3 [78,79].
Figure 3.
Figure 3.
(A) NotchICD activates genes by recruiting RBP-J and a histone acetyltransferase (HAT) complex that adds activating marks to histones, therefore allowing transcription on Notch target genes. In the absence of NotchICD, RBP2 can bind RBP-J and demethylate existing activating marks, leading to repression of Notch target genes [83]. (B) RBP2 has been shown to interact with the Sin3/HDAC complexes which are crucial targets for anti-cancer therapies [88-90].
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