Inhibiting an RBM39/MLL1 epigenomic regulatory complex with dominant-negative peptides disrupts cancer cell transcription and proliferation.

Abstract

RBM39 is a known splicing factor and coactivator. Here, we report that RBM39 functions as a master transcriptional regulator that interacts with the MLL1 complex to facilitate chromatin binding and H3K4 trimethylation in breast cancer cells. We identify RBM39 functional domains required for DNA and complex binding and show that the loss of RBM39 has widespread effects on H3K4me3 and gene expression, including key oncogenic pathways. RBM39's RNA recognition motif 3 (RRM3) functions as a dominant-negative domain; namely, it disrupts the complex and H3K4me trimethylation and expression of RBM/MLL1 target genes. RRM3-derived cell-penetrating peptides phenocopy the effects of the loss of RBM39 to decrease growth and survival of all major subtypes of breast cancer and yet are nontoxic to normal cells. These findings establish RBM39/MLL1 as a major contributor to the abnormal epigenetic landscape in breast cancer and lay the foundation for peptide-mediated cancer-specific therapy based on disruption of RBM39 epigenomic functions.

• Authors: Pavan Kumar Puvvula, Yao Yu, Kaelan Renaldo Sullivan, Henok Eyob, Julian Rosenberg, Alana Welm, Chad Huff, Anne M Moon
• Journal: Cell reports (Cell Rep) Vol. 35 Issue 9 Pg. 109156 (06 01 2021) ISSN: 2211-1247 [Electronic] United States
• PMID: 34077726 (Publication Type: Journal Article)
• Copyright: Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.

Chemical References

• Cell-Penetrating Peptides
• HCC1 autoantigen
• KMT2A protein, human
• Peptides
• RNA-Binding Proteins
• Myeloid-Lymphoid Leukemia Protein
• Histone-Lysine N-Methyltransferase

Topics

• Animals
• Breast Neoplasms (genetics, pathology)
• Carcinogenesis (pathology)
• Cell Line, Tumor
• Cell Nucleus (metabolism)
• Cell Proliferation (genetics)
• Cell Survival
• Cell-Penetrating Peptides (metabolism)
• Epigenomics
• Female
• HEK293 Cells
• Histone Code
• Histone-Lysine N-Methyltransferase (genetics, metabolism)
• Human Umbilical Vein Endothelial Cells (metabolism)
• Humans
• Mice, Inbred NOD
• Mice, SCID
• Myeloid-Lymphoid Leukemia Protein (genetics, metabolism)
• Peptides (metabolism)
• Phenotype
• Promoter Regions, Genetic (genetics)
• Protein Binding
• Protein Domains
• RNA-Binding Proteins (chemistry, genetics, metabolism)
• Transcription, Genetic