Correcting COMPASS dysfunction in cancer

An EZH2 inhibitor can be potentially used as an effective therapy for cancers with COMPASS-component mutations. The protein complex COMPASS (complex of proteins associated with SET1) contains a family of enzymes involved in the regulation of gene transcription. Among them, the lysine methyltransferase KMT2C (also known as MLL3) is frequently found mutated in various cancers. However, it remains unclear how these mutations may contribute to cancer and whether COMPASS dysfunction owing to MLL3 mutations can be therapeutically targeted. By examining patient data from The Cancer Genome Atlas (TCGA) database, Wang et al. identied hotspot mutations in the plant homeodomain (PHD) repeats of MLL3. Cancer patients carrying these hotspot mutations displayed reduced disease-free survival. To investigate why, the authors expressed and puried the MLL3 peptide region containing the hotspot locus and retrieved BAP1 and several BAP1 protein complex components as binding partners. Subsequent experiments showed that MLL3 hotspot mutations led to diminished BAP1 binding with MLL3. This, similarly to BAP1 loss, decreased the recruitment of MLL3 to enhancers, leading to decreased expression of multiple tumor suppressor genes. In line with this, depletion of MLL3 promoted tumor growth and shortened animal survival in breast cancer xenograft models. Interestingly, BAP1 deciency led to reduced expression of H3K27 demethylase UTX, another component of COMPASS, thereby promoting H3K27 trimethylation at enhancers of these tumor suppressor genes and silencing their expression. The specic EZH2 inhibitor GSK126 was able to eciently reverse MLL3 loss-induced H3K27 trimethylation and restore tumor suppressor expression in cancer cells. As a result, tumor cells or xenografts with MLL3 loss of function displayed enhanced responsiveness to this EZH2 inhibitor treatment, which correlated with extended overall survival in mice. It is intriguing that some mutations from one component of COMPASS will lead to decreased protein stability in other partners (such as UTX) in the same complex. It remains to be determined which tumor suppressors may mediate the effect of COMPASS dysfunction in cancer. In addition, it will be important to carry out clinical trials for the EZH2 inhibitor in cancer patients harboring MLL3 mutations to see whether they will benet from this potential therapeutic vulnerability. This important study provides proof of principle for the possibility of correcting cancer-associated COMPASS dysfunction using EZH2 inhibitors.