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CREB acts as a common transcription factor for major epigenetic repressors; DNMT3B, EZH2, CUL4B and E2F6

Cheemala Ashok1, Murugan Selvam1, Saravanaraman Ponne1

  • 1Department of Biotechnology, Pondicherry Central University, R. V. Nagar, Kalapet, Pondicherry, 605014, India.

Medical Oncology (Northwood, London, England)
|July 26, 2020
PubMed

Insights

The study reveals that CREB transcription factor activates key epigenetic repressors like DNMT3B, EZH2, and CUL4B. This finding highlights CREB as a potential therapeutic target in cancer due to its role in regulating these repressors.

Area of Science:

  • Molecular Biology
  • Epigenetics
  • Cancer Research

Background:

  • CREB signaling's role in cell proliferation is known, but its regulation of positive and negative regulators is unclear.
  • Epigenetic repressors (DNMT3B, EZH2, CUL4B) and their chromatin modification functions are well-studied.
  • Transcriptional regulation of these major epigenetic repressors remains poorly understood.

Purpose of the Study:

  • To investigate the transcriptional regulation of epigenetic repressors by CREB.
  • To identify CREB as a potential common transcription factor for DNMT3B, EZH2, CUL4B, and E2F6.
  • To establish the molecular link between CREB and epigenetic repressors in cancer cells.

Main Methods:

  • Computational tools and molecular techniques were employed.
  • Site-directed mutagenesis, promoter reporter assays, and chromatin immunoprecipitation (ChIP) were utilized.
  • pCREB binding to CREs in the promoters of target genes was confirmed via ChIP.

Main Results:

  • CREB was identified as a common transcription factor for DNMT3B, EZH2, CUL4B, and E2F6.
  • pCREB binding to CREs on the promoters of these repressors was demonstrated, inducing their transcription.
  • CREB overexpression increased repressor expression and associated marks (H3K27me3, H2AK119ub), while knockdown decreased them in cancer cells.

Conclusions:

  • CREB transcriptionally activates major epigenetic repressors, including DNMT3B, EZH2, and CUL4B.
  • The study establishes a molecular relationship between CREB and these epigenetic repressors.
  • CREB's role in regulating these repressors suggests it is a significant therapeutic target for various cancers.
Keywords:
CRECREBCUL4BDNMT3BE2F6EZH2cAMP responsive element

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