UTX Mutations in Human Cancer

Abstract

Ubiquitously transcribed tetratricopeptide repeat on chromosome X (UTX, encoded by KDM6A) is a histone demethylase that targets di- and tri-methylated histone H3 lysine 27 (H3K27). UTX function has been linked to homeotic gene expression, embryonic development, and cellular reprogramming. UTX and its protein interactors within the COMPASS family, including the MLL3 and MLL4 lysine methyltransferases, are frequently mutated in multiple human cancers; however, the molecular basis of how these mutations contribute to oncogenesis remains unclear. Here, we discuss catalytic-dependent and -independent functions of UTX and its partners MLL3 and MLL4 as part of the COMPASS family during development and in oncogenesis.

Keywords: UTX; cancer; chromatin; gene expression; transcription.

Figure 1. Human UTX and UTY

(A) Chromosomal localization of KDM6A, UTY, and KDM6B. (B) Domain organization of human UTX and UTY proteins. The similarity (aligned score) for the tetratricopeptide repeats (TPR) domain and the Jumonji C (JmjC) domain of UTX and UTY was calculated by ClustalW sequence alignment. (C) The aligned score for similarity between UTX, UTY, and JMJD3 was calculated by ClustalW sequence alignment.

Figure 2. Crystal Structure of the Catalytic Domain of UTX and UTY Proteins

(A) The catalytic fragment of UTX bound with histone H3K27me3 peptide, N-oxyalylglycine, and Ni (II), modified from PDB: 3AVR (Sengoku and Yokoyama, 2011). (B) The crystal structure of JmjC domain of human UTY, modified from PDB: 3ZLI (Walport et al., 2014).

Figure 3. UTX Functions within an SPT6 Complex and the MLL3/4 COMPASS Family

(A) SPT6 enhances transcriptional elongation by tethering UTX to elongating RNA polymerase II (Pol II). Shown with SPT6, Pol II, and UTX are SETD2, the H3K36 methyltransferase that also interacts with elongating Pol II, and P-TEFb-containing super elongation complex (SEC). (B) UTX associates with and functions in the MLL3/MLL4 COMPASS family, and these complexes implementing H3K4me1 and demethylating H3K27me3 are essential for enhancer activity. (C) Size-exclusion chromatography of nuclear extract from HEK293T cells probed for UTX and components of the COMPASS family, suggesting that UTX may participate in non-COMPASS complexes.

Figure 4. UTX Mutations in Human Cancers

(A) Distribution of all KDM6A mutations that occur within the UTX protein coding region and UTY mutations that occur within the UTY protein coding region from cBioPortal. The red, green, and blue boxes indicate computationally identified TPR motifs while the yellow box indicates the JmjC domain. (B) KDM6A mutation frequencies across various human cancer types as obtained from cBioPortal.

Figure 5. Mutations in UTX-Associated MLL3/MLL4 COMPASS Family

In normal cells, the UTX/MLL3 COMPASS complex is recruited by tumor-suppressive factors, such as BAP1 complex to enhancers, and controls the expression of multiple tumor suppressors (Wang et al., 2018). In tumor cells, mutations occurring in the MLL3-PHD domain lead to dissociation between UTX/MLL3 COMPASS and BAP1 complex (left). UTX mutations (right) that disrupt the interaction between UTX and COMPASS may also affect the proper function of these complexes and thus contribute to tumorigenesis.

Figure 6. Balance between Functional UTX and PRC2 as a Targeted Therapy for Human Cancer

Balance between UTX/COMPASS and PRC2 complexes in the setting of histone H3 lysine 27 methylation levels (top). Inactivating mutations of UTX or gain-of-function EZH2 mutations result in an oncogenic advantage for PRC2 (bottom). Resetting the epigenetic balance by targeting the polycomb complex or stabilizing UTX and its associated factors could be a strategy for treating human cancers resulting from UTX/COMPASS or PRC2 mutations.