Histone demethylases in physiology and cancer: a tale of two enzymes, JMJD3 and UTX

Abstract

Gene regulation is fine-tuned by a dynamic balance between transcriptionally activating and repressive modifications of histone tails. It has been well-established that lysine and arginine methylation can be reversed by two groups of evolutionarily conserved enzymes known as histone demethylases, which have been shown to play critical roles in development, differentiation and diseases like cancer. Recent work has demonstrated demethylase-independent functions of these proteins, highlighting the complex mechanisms by which these proteins exert their effects on gene expression. Here, we discuss the roles of lysine 27 demethylases, JMJD3 and UTX, in cancer and potential therapeutic avenues targeting these enzymes. Despite a high degree of sequence similarity in the catalytic domain between JMJD3 and UTX, numerous studies revealed surprisingly contrasting roles in cellular reprogramming and cancer, particularly leukemia. Understanding the demethylase-dependent and demethylase-independent functions of the enzymes affecting histone methylation, their post-translational modifications and participation in different complexes, as well as in vivo modeling of the mutations affecting those enzymes in cancer, can shed light on their unique physiological roles. This information cumulated in the future will aid in the development of improved inhibitors to treat cancers affected by demethylase mutations and aberrant gene activation.

Fig. 1

Main enzymes with demethylase activity against lysine 27 methylation and other non-demethylase functions. A) JMJD3 and UTX are the two best-characterized H3K27me3 demethylases. The UTX paralog, UTY, has very weak, albeit detectable, demethylase activity due to a point mutation in the JmjC catalytic domain. KIAA1718 has demethylase activity against multiple lysine residues, including lysine 9 and 27 on histone H3. JmjC: Jumonji C domain, TPR: tetratricopeptide repeats, PHD: plant homeodomain, aa: amino acids. B) Apart from direct histone demethylation, H3K27 demethylases can also participate in complexes or interact with enzymes that affect histone lysine methylation, chromatin remodeling, transcriptional elongation and protein ubiquitination. Lysine methylation levels can also affect genomic interactions and gene expression programs in a three-dimensional fashion. MLL: mixed-lineage leukemia, SWI/SNF: switch/sucrose non-fermentable, AR: androgen receptor, PRC1: polycomb repressor complex 1, TRIM26: tripartite motif (family) 26, PHF20: plant homeodomain factor 20.

Fig. 2

Schematic diagram of the protein UTX showing loss-of-function mutations in different cancer types. Red squares denote mutations identified in acute lymphoblastic leukemia, blue circles correspond to bladder cancer mutations, and black triangles denote chronic myelomonocytic leukemia (CMML) cases. del: deletion, fs: frameshift, sj: splice junction, X: stop codon.