Histone deacetylase inhibitor-induced cancer stem cells exhibit high pentose phosphate pathway metabolism

Oncotarget. 2016 May 10;7(19):28329-39. doi: 10.18632/oncotarget.8631.


Purpose: We recently demonstrated that histone deacetylase (HDAC) inhibitors can "reprogram" differentiated triple-negative breast cancer cells to become quiescent stem-like cancer cells. We hypothesized that the metabolic state of such cells differs from that of their differentiated progeny.

Results: In untreated cells, glucose uptake was higher in ALDH+ cells than in ALDH- cells (p = 0.01) but lactate production was not different; treating ALDH- or ALDH+ cells with VA or SAHA similarly increased glucose uptake without changing lactate production but upregulated G6PD, a rate-limiting enzyme in pentose phosphate pathway metabolism. NADPH production was higher in HDAC inhibitor-treated stem-like cells than in vehicle-treated cells (p < 0.05). Two G6PD inhibitors, 6-aminonicotinamide and dehydroepiandrosterone, decreased mammosphere formation efficiency and ALDH activity and 6-aminonicotinamide reduced the VA-induced increase in ALDH+ cells. Finally, patients expressing high G6PD mRNA had significantly worse overall survival (p < 0.001), and patients with high G6PD protein showed a similar trend towards worse disease-specific survival (p = 0.06).

Methods: Glucose consumption, lactate and NADPH production, and reactive oxygen species generation were compared in aldehyde dehydrogenase (ALDH)-positive and -negative cells in the presence or absence of the HDAC inhibitors valproic acid (VA) or suberoylanilide hydroxamic acid (SAHA). Glucose-6-phosphate dehydrogenase (G6PD) expression was evaluated in a tissue microarray from 94 patients with node-positive invasive breast carcinoma and in two publically available databases and correlated with overall survival.

Conclusions: Energy metabolism in HDAC inhibitor-induced stem-like cancer cells differed sharply from that of differentiated cell types. HDAC inhibitor-induced dedifferentiation promoted metabolic reprogramming into the pentose phosphate pathway, which is targeted effectively by G6PD inhibition. These findings highlight a potential dual-therapy approach to targeting bulk differentiated cells with HDAC inhibitors and CSCs with G6PD inhibitors.

Keywords: G6PD; HDAC inhibitors; cancer stem cells; pentose phosphate pathway.

MeSH terms

  • Cell Dedifferentiation / drug effects*
  • Cell Line, Tumor
  • Female
  • Glucosephosphate Dehydrogenase / metabolism
  • Histone Deacetylase Inhibitors / pharmacology*
  • Humans
  • Neoplastic Stem Cells / drug effects*
  • Neoplastic Stem Cells / metabolism*
  • Pentose Phosphate Pathway / drug effects
  • Triple Negative Breast Neoplasms / metabolism*
  • Triple Negative Breast Neoplasms / pathology


  • Histone Deacetylase Inhibitors
  • Glucosephosphate Dehydrogenase