GSE115988
Specific inhibition of DPY30 activity by peptides suppresses blood cancer cell growth
Epigenetic modulators are being recognized as attractive targets for potential cancer treatment. SET1/MLL complexes are the major H3K4 methyltransferase complexes in mammals. The DPY30 subunit is associated with these complexes by forming a dimer that directly binds to the ASH2L subunit in the complexes and facilitates methylation. We have previously established an important role of DPY30 in certain hematologic malignancies including MLL-rearranged leukemia and Burkitt's lymphoma, but the domain on DPY30 that regulates cancer growth is not evident. Moreover, the potential of pharmacologically targeting this chromatin modulator to inhibit cancer has not been explored. Here we have developed a peptide-based strategy to specifically target DPY30 activity. We have designed cell-penetrating peptides that can either bind to DPY30 or show defective or enhanced binding to DPY30. The DPY30-binding peptides, but not the non-binding peptide, inhibit DPY30's activity in interacting with ASH2L and in enhancing H3K4 methylation. Treatment with the DPY30-binding, but not the non-binding, peptide significantly inhibited the growth of MLL-rearranged leukemia and other MYC-dependent hematologic cancer cells including Burkitt's lymphoma cells. These results strongly support a critical role of the ASH2L-binding groove of DPY30 in promoting the growth of certain blood cancers, and also demonstrate a proof-of-principle for the feasibility of pharmacologically targeting the ASH2L-binding groove of DPY30 for potential cancer inhibition. Overall design: Samples are RNA-seq from peptide treated cancer cell lines. Y518R peptide binds DPY30 while 3R peptide does not bind DPY30.