MLL3 Mutations Disrupt COMPASS Recruitment to Enhancer Chromatin

MLL3 is a lysine methyltransferase subunit of the COMPASS complex responsible for monomethylation of histone H3 lysine 4 (H3K4). MLL3 is frequently mutated in a variety of tumor types, but the mechanism by which these mutations promote tumorigenesis remains unclear, prompting Wang and colleagues to investigate the role of MLL3 mutations in cancer. Analysis of data from The Cancer Genome Atlas revealed two MLL3 mutational hotspots within the N-terminal PHD finger repeats that are associated with cancer. Mass spectrometry showed that this N-terminal region of MLL3 interacted with the histone deubiquitinating BAP1 complex, whereas other COMPASS family proteins did not interact with BAP1. In patients with breast cancer, MLL3 mutations in the PHD repeats were associated with reduced disease-free survival, and, in breast cancer cells, these mutations reduced the interaction between MLL3 and BAP1. Further, MLL3 PHD domain mutations were identified in lung adenocarcinoma, bladder carcinoma, breast cancer, and colon adenocarcinoma. Mechanistically, BAP1 recruited MLL3 to enhancer chromatin to promote H3K4 monomethylation. Thus, deletion of BAP1 or mutation of the MLL3 PHD domain reduced MLL3 activity at enhancers. MLL3 depletion decreased expression of tumor suppressor genes from BAP1-dependent enhancers and accelerated the growth of breast cancer xenografts. MLL3 mutations or BAP1 deficiency also reduced recruitment of the H3K27 demethylase KDM6A, a component of MLL3-COMPASS, to enhancers, thereby increasing H3K27 trimethylation. Consistent with these findings, using an EZH2 inhibitor to block the H3K27 methyltransferase activity of PRC2 restored normal gene expression patterns in MLL3-mutant cells, and reduced tumor growth and extended survival in vivo. In addition to elucidating a mechanism by which MLL3 mutations may contribute to oncogenesis, these findings suggest the potential for therapeutic targeting of EZH2 in tumors with COMPASS subunit mutations.

Wang L, Zhao Z, Ozark PA, Fantini D, Marshall SA, Rendleman EJ, et al. Resetting the epigenetic balance of Polycomb and COMPASS function at enhancers for cancer therapy. Nat Med 2018;24:758–69.

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