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HDAC1 and HDAC2 integrate the expression of p53 mutants in pancreatic cancer

N Stojanovic1, Z Hassan1, M Wirth1

  • 1II. Medizinische Klinik, Technische Universität München, München, Germany.

Oncogene
|October 11, 2016
PubMed

Insights

Targeting histone deacetylases HDAC1 and HDAC2 reduces mutant p53 expression in pancreatic cancer. This class I HDAC-dependent control of the TP53 gene involves MYC and offers a new therapeutic strategy.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Genetics

Background:

  • Mutant p53 proteins drive pancreatic cancer progression by losing tumor-suppressive functions and gaining oncogenic activities.
  • Mutant p53 represents a critical therapeutic target in pancreatic ductal adenocarcinoma.
  • The precise mechanisms maintaining mutant p53 expression remain incompletely understood.

Purpose of the Study:

  • To investigate the role of class I histone deacetylases (HDAC1 and HDAC2) in regulating mutant p53 expression in pancreatic cancer.
  • To explore the potential of targeting HDAC1/HDAC2 as a therapeutic strategy against mutant p53 in pancreatic cancer.

Main Methods:

  • Utilized human and murine pancreatic cancer cell lines.
  • Administered small molecule HDAC inhibitors (HDACi) and employed genetic elimination of HDAC1 and HDAC2.
  • Performed molecular analyses including mRNA and protein level quantification.
  • Investigated protein-DNA interactions using chromatin immunoprecipitation assays to assess binding of HDAC1, HDAC2, and MYC to the TP53 gene.

Main Results:

  • Class I HDACs (HDAC1 and HDAC2) were found to be crucial for maintaining mutant p53 mRNA and protein expression.
  • Inhibition or genetic depletion of HDAC1/HDAC2 led to significant reductions in mutant p53 levels.
  • HDAC1, HDAC2, and MYC were identified as direct binders to the TP53 gene locus.
  • HDAC inhibitor treatment resulted in decreased MYC recruitment to the TP53 gene.

Conclusions:

  • Class I HDACs (HDAC1/HDAC2) exert previously unrecognized control over TP53 gene expression, influencing mutant p53 levels in pancreatic cancer.
  • MYC plays a contributing role in this HDAC-dependent regulation.
  • Combined targeting of HDAC1/HDAC2 and MYC presents a novel molecularly defined strategy for treating pancreatic cancer harboring mutant p53.

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