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Induction of HDAC2 expression upon loss of APC in colorectal tumorigenesis

Ping Zhu1, Elke Martin, Jörg Mengwasser

  • 1Institute of Toxicology and Genetics, Forschungszentrum Karlsruhe Branch, H.-v.-H.-Platz 1, D-76344 Eggenstein, Germany.

Cancer Cell
|May 18, 2004
PubMed

Insights

Faulty expression of histone deacetylase 2 (HDAC2) drives colon cancer by preventing cell death. Inhibiting HDAC2 with valproic acid reduced tumor formation in mice, suggesting HDAC2 as a potential cancer therapy target.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • Histone deacetylases (HDACs) are implicated in leukemia development through aberrant transcriptional repression.
  • The role of specific HDACs in solid tumor development, particularly colon cancer, remains less understood.

Purpose of the Study:

  • To investigate the role of a specific transcriptional repressor in solid tumor development.
  • To determine the involvement of histone deacetylase 2 (HDAC2) in colon cancer pathogenesis.
  • To evaluate HDAC2 as a potential therapeutic target for colon cancer.

Main Methods:

  • Analysis of HDAC2 expression in human colon cancer samples and APC-deficient mouse models.
  • Investigating the regulatory pathways (Wnt, c-Myc) influencing HDAC2 expression upon loss of the adenomatosis polyposis coli (APC) tumor suppressor.
  • Assessing the effect of HDAC2 inhibition using valproic acid on tumor formation in APC(min) mice.
  • Evaluating HDAC2's role in colon cancer cell apoptosis.

Main Results:

  • Loss of the APC tumor suppressor induces HDAC2 expression, dependent on the Wnt pathway and c-Myc.
  • Elevated HDAC2 expression is prevalent in human colon cancer tissues and APC-deficient mouse models.
  • HDAC2 is essential for preventing apoptosis in colonic cancer cells.
  • Valproic acid treatment significantly reduced adenoma formation in APC(min) mice.

Conclusions:

  • HDAC2 plays a critical role in colon cancer progression by inhibiting apoptosis.
  • Targeting HDAC2, potentially with drugs like valproic acid, shows promise for colon cancer therapy.

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