Colon cancer cells maintain low levels of pyruvate to avoid cell death caused by inhibition of HDAC1/HDAC3

Muthusamy Thangaraju, Kristina N. Carswell, Puttur D Prasad, Vadivel Ganapathy

Research output: Contribution to journalArticle

88 Citations (Scopus)

Abstract

Human colon cancer cells and primary colon cancer silence the gene coding for LDH (lactate dehydrogenase)-B and up-regulate the gene coding for LDH-A, resulting in effective conversion of pyruvate into lactate. This is associated with markedly reduced levels of pyruvate in cancer cells compared with non-malignant cells. The silencing of LDH-B in cancer cells occurs via DNA methylation, with involvement of the DNMTs (DNA methyltransferases) DNMT1 and DNMT3b. Colon cancer is also associated with the expression of pyruvate kinase M2, a splice variant with low catalytic activity. We have shown recently that pyruvate is an inhibitor of HDACs (histone deacetylases). Here we show that pyruvate is a specific inhibitor of HDAC1 and HDAC3. Lactate has no effect on any of the HDACs examined. Colon cancer cells exhibit increased HDAC activity compared with non-malignant cells. HDAC1 and HDAC3 are up-regulated in colon cancer cells and in primary colon cancer, and siRNA (small interfering RNA)-mediated silencing of HDAC1 and HDAC3 in colon cancer cells induces apoptosis. Colon cancer cells silence SLC5A8, the gene coding for a Na+-coupled pyruvate transporter. Heterologous expression of SLC5A8 in the human colon cancer cell line SW480 leads to inhibition of HDAC activity when cultured in the presence of pyruvate. This process is associated with an increase in intracellular levels of pyruvate, increase in the acetylation status of histone H4, and enhanced cell death. These studies show that cancer cells effectively maintain low levels of pyruvate to prevent inhibition of HDAC1/HDAC3 and thereby to evade cell death.

Original languageEnglish (US)
Pages (from-to)379-389
Number of pages11
JournalBiochemical Journal
Volume417
Issue number1
DOIs
StatePublished - Jan 1 2009

Fingerprint

Cell death
Pyruvic Acid
Colonic Neoplasms
Cell Death
Cells
Histone Deacetylases
Genes
Lactic Acid
Acetylation
Pyruvate Kinase
Neoplasms
Methyltransferases
Neoplasm Genes
DNA Methylation
Histones
RNA Interference
Small Interfering RNA
Catalyst activity
Up-Regulation
Apoptosis

Keywords

  • Cancer cell death
  • Histone deacetylase (HDAC)
  • Lactate dehydrogenase (LDH)
  • Pyruvate
  • Pyruvate kinase
  • SLC5A8

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology
  • Medicine(all)

Cite this

Colon cancer cells maintain low levels of pyruvate to avoid cell death caused by inhibition of HDAC1/HDAC3. / Thangaraju, Muthusamy; Carswell, Kristina N.; Prasad, Puttur D; Ganapathy, Vadivel.

In: Biochemical Journal, Vol. 417, No. 1, 01.01.2009, p. 379-389.

Research output: Contribution to journalArticle

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