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

Pavan Kumar Puvvula1, Yao Yu2, Kaelan Renaldo Sullivan1

  • 1Department of Molecular and Functional Genomics, Weis Center for Research, Geisinger Clinic, Danville, PA, USA.

Cell Reports
|June 2, 2021
PubMed

Insights

Ribonucleoprotein methyltransferase like 1 (RBM39) acts as a master regulator of transcription, interacting with the MLL1 complex to influence gene expression and H3K4 trimethylation in breast cancer. Disrupting RBM39 with peptides inhibits cancer cell growth without harming normal cells.

Area of Science:

  • Molecular Biology
  • Epigenetics
  • Cancer Research

Background:

  • Ribonucleoprotein methyltransferase like 1 (RBM39) is recognized as a splicing factor and coactivator.
  • Its precise role in transcriptional regulation, particularly in cancer, requires further elucidation.

Purpose of the Study:

  • To investigate the function of RBM39 as a transcriptional regulator in breast cancer.
  • To identify RBM39 domains critical for its function and interaction with the MLL1 complex.
  • To explore the therapeutic potential of targeting RBM39.

Main Methods:

  • Chromatin immunoprecipitation assays to assess MLL1 complex binding and H3K4 trimethylation.
  • Gene expression analysis to determine the impact of RBM39 loss.
  • Functional domain analysis of RBM39.
  • Development and testing of RRM3-derived cell-penetrating peptides.

Main Results:

  • RBM39 functions as a master transcriptional regulator, interacting with the MLL1 complex to promote chromatin binding and H3K4 trimethylation in breast cancer cells.
  • Loss of RBM39 significantly alters H3K4me3 levels and gene expression, impacting oncogenic pathways.
  • The RNA recognition motif 3 (RRM3) of RBM39 acts as a dominant-negative domain, disrupting the RBM39/MLL1 complex and target gene expression.
  • RRM3-derived peptides mimic RBM39 loss, reducing breast cancer cell growth and survival across subtypes with minimal toxicity to normal cells.

Conclusions:

  • RBM39 and the MLL1 complex are key players in the aberrant epigenetic landscape of breast cancer.
  • Targeting RBM39 epigenomic functions via RRM3-derived peptides offers a promising strategy for cancer-specific therapy.
Keywords:
CAPERalphaMLL1RBM39breast cancerpathologic coactivatortherapeutic cell-penetrating peptide

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