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 DPY30's 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.

• Authors: Kushani K Shah, Robert H Whitaker, Theodore Busby, Jing Hu, Bi Shi, Zhenjia Wang, Chongzhi Zang, William J Placzek, Hao Jiang
• Journal: Experimental cell research (Exp Cell Res) Vol. 382 Issue 2 Pg. 111485 (09 15 2019) ISSN: 1090-2422 [Electronic] United States
• PMID: 31251903 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.

Chemical References

• ASH2L protein, human
• DNA-Binding Proteins
• DPY30 protein, human
• Nuclear Proteins
• Peptides
• Transcription Factors

Topics

• Amino Acid Sequence
• Cell Proliferation (drug effects)
• DNA-Binding Proteins (chemistry)
• Epigenesis, Genetic (drug effects)
• Gene Expression Profiling
• Humans
• Leukemia (drug therapy, pathology)
• Nuclear Proteins (chemistry)
• Peptides (chemistry, pharmacology, therapeutic use)
• Transcription Factors (chemistry)