Specific inhibition of DPY30 activity by ASH2L-derived peptides suppresses blood cancer cell growth

Abstract

DPY30 facilitates H3K4 methylation by directly binding to ASH2L in the SET1/MLL complexes and plays an important role in hematologic malignancies. However, the domain on DPY30 that regulates cancer growth is not evident, and 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 derived from ASH2L that can either bind to DPY30 or show defective or enhanced binding to DPY30. The DPY30-binding peptides specifically inhibit its activity in interacting with ASH2L and enhancing H3K4 methylation. Treatment with the DPY30-binding peptides significantly inhibited the growth of MLL-rearranged leukemia and other MYC-dependent hematologic cancer cells. We also revealed subsets of genes that may mediate the effect of the peptides on cancer cell growth, and showed that the DPY30-binding peptide sensitized leukemia to other types of epigenetic inhibitors. These results strongly support a critical role of the ASH2L-binding groove of DPY30 in promoting blood cancers, and demonstrate a proof-of-principle for the feasibility of pharmacologically targeting the ASH2L-binding groove of DPY30 for potential cancer inhibition.

Alternative approaches to target Myc for cancer treatment

“…Considering its currently limited inhibitors including ASH2L-derived peptides, the question is how to find eligible inhibitors to target Dpy30. 83,84 Similarly, another core subunit of chromatin remodeler, namely BPTF, is also a necessary component for the activation of the complete Myc transcription activity in fibroblasts. 85 Moreover, BPTF expression positively correlates with MYC-induced transcriptome signatures in multiple cancer types in humans, such as BL, colorectal, prostate, and pancreatic carcinomas.…”

Analyzing the impact of CFP1 mutational landscape on epigenetic signaling

“…Inhibition of the DPY30 interaction with Ash2L blunts blood cancer cell growth. 101 Similarly, small molecule inhibitors targeting the WIN binding pocket of WDR5, 102 which interacts with MLL1, and to a lesser extent, to other members of the KMT2 family of enzymes, 103,104 blocks the proliferation of mixed-lineage leukemia cells by inhibiting MLL1 activity. 105 As a critical regulator of SETD1A/B COMPASS, CFP1 could also become a potential target for inhibiting SETD1A/B signaling in carcinogenesis.…”

A new biology of cell penetrating peptides

“…We present here a succinct summary of additional publications, which investigate and exploit the tremendous biomedical potential of bioportides in their various structural guises (Figure 1D). Clearly, the broad scope of potential applications of cell permeable bioactive peptides, ranging from epigenetic modulation [ 87 ] to the blockade of Toll‐like receptor (TLR) signalling, [ 88 ] suggests a very healthy future for such technologies.…”

“…Moreover, DPY30, significantly upregulated in some Burkitt's lymphoma samples, [ 89 ] enhances the methylation activity of SET1/MLL complexes by directly binding a relatively short 14 AA C‐terminal segment of the ASH2L subunit. [ 87 ] A sychnologic bioportide (TAT‐HA‐ASH2L), combining the CPP Tat with an HA epitope tag and ASH2L 510‐529 , binds DPY30 to block its interaction with ASH2L and significantly inhibit the growth of MLL ‐rearranged leukaemia and other haematological cancer cells. [ 87 ] A similar sychnologic strategy was employed to generate TIP1, [ 88 ] a bioportide combining penetratin with a sequence derived from the Toll/interleukin‐1 receptor (TIR) domain‐containing adaptor protein (SHCRVLLI).…”

“…[ 87 ] A sychnologic bioportide (TAT‐HA‐ASH2L), combining the CPP Tat with an HA epitope tag and ASH2L 510‐529 , binds DPY30 to block its interaction with ASH2L and significantly inhibit the growth of MLL ‐rearranged leukaemia and other haematological cancer cells. [ 87 ] A similar sychnologic strategy was employed to generate TIP1, [ 88 ] a bioportide combining penetratin with a sequence derived from the Toll/interleukin‐1 receptor (TIR) domain‐containing adaptor protein (SHCRVLLI). TIP1 specifically binds the BB loop of the TLR4‐TIR domain to inhibit multiple TLR signalling pathways and has therapeutic potential for the treatment of TLR‐mediated autoimmune and inflammatory diseases.…”