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Bromodomain and extra-terminal domain inhibition modulates the expression of pathologically relevant microRNAs in

Afua A Mensah1, Luciano Cascione1,2,3, Eugenio Gaudio1

  • 1Università della Svizzera italiana (USI), Institute of Oncology Research (IOR), Bellinzona, Switzerland.

Haematologica
|August 5, 2018
PubMed

Insights

Bromodomain and extra-terminal domain (BET) inhibitors, like OTX015, alter microRNA expression in lymphoma cells. These inhibitors directly impact microRNA genes by reducing BRD4 binding, offering new therapeutic strategies for lymphomagenesis.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • Aberrant microRNA expression is implicated in lymphomagenesis.
  • Bromodomain and extra-terminal domain (BET) inhibitors show promise in treating hematologic malignancies.
  • OTX015 is a BET inhibitor with demonstrated preclinical and clinical activity.

Purpose of the Study:

  • To investigate the impact of OTX015 on microRNA expression in diffuse large B-cell lymphoma (DLBCL).
  • To elucidate the role of BRD4 in regulating microRNA expression in DLBCL.
  • To explore the relationship between BET inhibition, PRMT5, and microRNA modulation in lymphoma.

Main Methods:

  • MicroRNA profiling of DLBCL cells treated with OTX015.
  • Analysis of publicly available chromatin immunoprecipitation sequencing (ChIP-seq) data for BRD4 binding in DLBCL cells.
  • Correlation analysis between microRNA expression changes and BRD4 binding patterns following BET inhibition.

Main Results:

  • OTX015 treatment altered the expression of specific microRNAs, including miR-92a-1-5p, miR-21-3p, miR-155-5p, and miR-96-5p.
  • BET inhibitors, including OTX015 and JQ1, reduced BRD4 binding to microRNA regulatory regions.
  • Downregulated microRNAs showed decreased BRD4 binding, suggesting direct transcriptional regulation by BRD4.
  • BET inhibitor treatment also decreased PRMT5 expression, which negatively regulates miR-96-5p transcription.

Conclusions:

  • BET inhibitors directly modulate microRNA expression in lymphoma by influencing BRD4 binding to microRNA gene promoters.
  • The findings reveal a novel mechanism by which BET inhibitors impact lymphomagenesis through microRNA regulation.
  • These results suggest that targeting BRD4 and its downstream microRNA effects could be a viable therapeutic strategy for lymphoma.

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