A Histone Modifier's Phase Separation Is Needed for Antitumor Function

Nonsense or missense mutations in KDM6A that disrupt the protein it encodes, UTX, are common in human cancers. Perplexingly, although UTX is known for its function as a histone 3 lysine 27 (H3K27) demethylase, the ability of UTX to act as a tumor suppressor typically does not depend on its histone demethylase activity, raising questions about what other roles this protein may play. Shi, Li, Song, Wang, and colleagues discovered that a core intrinsically disordered region (cIDR), comprised by residues 549 through 848, was capable of forming micrometer-sized condensates via liquid–liquid phase separation. In KDM6A-null acute myeloid leukemia and pancreatic cancer cell lines, introduction of wild-type UTX resulted in the formation of nuclear foci and reduced cancer cell growth. However, introduction of UTX with the truncation mutation most common in human cancers (UTX_1–554)—which retains the tetratricopeptide repeat domains (TPR) required for interaction between UTX and its binding partner MLL4 (a H3K4 methyltransferase) but lacks the cIDR—failed to produce this tumor-suppressive effect. Notably, condensates between UTX and MLL4 failed to form not only when UTX lacked its TPR, as anticipated, but also when UTX lacked its cIDR. Further in vitro analyses in live cells showed that the ability of UTX to form nuclear condensates promoted MLL4 recruitment and was essential for its ability to promote H3K27 demethylation. Importantly, by concentrating MLL4 into discrete compartments on chromatin, UTX condensates may perform a critical role in enhancing MLL4-mediated propagation of H3K4me marks. Interestingly, UTY, the Y chromosome homolog of UTX, forms more solid-like and less dynamic condensates. The weaker tumor-suppressive activity of UTY associated with its altered biophysical properties of condensates may contribute to the male predominance of cancer. Collectively, these findings provide key mechanistic insight into how wild-type UTX modulates chromatin states to suppress the development of cancer and how mutations that disrupt its ability to phase separate may perturb this balance.

Shi B, Li W, Song Y, Wang Z, Ju R, Ulman A, et al. UTX condensation underlies its tumour-suppressive activity. Nature 2021;597:726–31.

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