PROJECT SUMMARY It remains incompletely understood why men are more likely to get and die from cancer than women. Tumor suppressor genes that escape from X-inactivation substantially contribute to the lower cancer incidence in females. Some of these genes, including UTX/KDM6A, have Y- chromosome homologs, but human cancer genetics suggest that the Y homologs are less tumor- suppressive than their X-chromosome counterparts, such that the X-X pairs are more tumor- suppressive than the X-Y homologs. This activity bias contributes to the cancer sex dimorphism, but its underlying molecular mechanisms are unknown. In our preliminary studies, we found that the UTX undergoes liquid-liquid phase separation that is mediated by its core Intrinsically Disordered Region (cIDR), and this property is critical for its tumor suppressive activity by co- condensing MLL4 and its H3K4 mono-methylation activity into the same droplets on chromatin and greatly enhances. We then found that cIDR is the key determinant of the lower tumor suppressive activity of UTY. UTY cIDR has a stronger propensity than UTX cIDR to form condensates, but UTY condensates are less dynamic than UTX condensates. Our results allow us to formulate and further test our central hypothesis that natural variations in the UTX and UTY condensate properties affect their tumor suppressive activity and contribute to male bias in cancer. Specific Aim 1. Determine the contribution of UTY cIDR to its weaker tumor suppressive activity. Specific Aim 2: Link the differential condensate properties to differential tumor suppressive activities through identification of key determinant in UTY cIDR. These studies will lay foundation for follow-up in-depth studies, which will establish a new concept that key and variations related to a fundamental principle of cellular organization contribute to the sexual dimorphisms in cancer incidence.

PROJECT NARRATIVE It remains poorly understood why men are more likely to get and die from cancer than women. This project investigates how the biophysical properties of a key tumor suppressive protein differ between the male and female homologs and influence the activity in suppressing cancer. Knowledge from this project will improve our understanding of the molecular mechanisms underlying the sex bias in cancer and will have implications in developing novel strategies in cancer therapeutics.