In the Ezh2 null genotype, 2D cell lines had marked derepression of Hox genes, but in 3D tumor spheroids, Ezh2 null cells were able to continue to repress Hox genes and instead showed derepression of Foxp2. Together, these findings underscore the power of using 3D systems for genetic, epigenetic and drug validation experimentation in cancer research. Here, EZH2 is linked to cancer.