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Northwestern Medicine study has identified an epigenetic imbalance that silences the expression of tumor-suppressing proteins, allowing cancerous cells to proliferate. In the study, researchers applied a simple molecular inhibitor that reversed epigenetic imbalance in laboratory models. This inhibitor has a potential therapeutic application, and the study will be followed by a clinical trial led by Northwestern researchers.
Though mutations in a gene-MLL3 are common across many types of cancers, mutations in MLL3, a component of a complex named COMPASS discovered by Shilatifard’s laboratory, were one of the most frequently identified mutations in cancer, according to an analysis of publically available genomic data performed as part of the current study.
Among all of the histone modifiers and transcription factors analyzed, the protein has significant hot-spot mutations- it was present in 7 percent of primary tumors and in metastatic tumors with higher mutation rate. The presence of MLL3 hot-spot mutations was correlated with significantly lower cancer survival rates, indicating there was some oncogenic mechanism triggered by the mutations.
After a series of biochemical experiments, they got success when examining the relationship between MLL3 and a molecule complex called PRC2. MLL3, as part of COMPASS, normally promotes the expression of numerous tumor-suppressing genes that are immediately downstream.
However, the study found that if there are specific mutations in MLL3, it will not be recruited to the right location on the genome. Instead, PRC2 becomes dominant and prevents downstream tumor-suppressor gene expression. Applying a small PRC2 inhibitor, preventing PRC2 from silencing the downstream tumor-suppressor genes, researchers were able to restore normal function and slow tumor growth.
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