Abstract
BackgroundHistone deacetylase (HDAC) inhibitors are promising anticancer drugs but their effect on tumor treatment has been disappointing mainly due to the acquisition of HDAC inhibitor resistance. However, the mechanisms underlying such resistance remain unclear.MethodsIn this study, we performed Western blot, q-PCR, and promoter assay to examine the expression of HDAC inhibitor-induced phospholipase D2 (PLD2) in MDA-MB231and MDA-MB435 breast cancer cells. Apoptosis and proliferation were analyzed by flow cytometry. In addition to invasion and migration assay, angiogenesis was further measured using in vitro tube formation and chick embryo chorioallantoic membrane model.ResultsHDAC inhibitors including suberoylanilide hydroxamic acid (SAHA), trichostatin, and apicidin, induce expression of PLD2 in a transcriptional level. SAHA upregulates expression of PLD2 via protein kinase C-ζ in breast cancer cells and increases the enzymatic activity of PLD. The combination treatment of SAHA with PLD2 inhibitor significantly enhances cell death in breast cancer cells. Phosphatidic acid, a product of PLD activity, prevented apoptosis promoted by cotreatment with SAHA and PLD2 inhibitor, suggesting that SAHA-induced PLD2 expression and subsequent activation of PLD2 might confers resistance of breast cancer cells to HDAC inhibitor. The combinational treatment of the drugs significantly suppressed invasion, migration, and angiogenesis, compared with that of either treatment.ConclusionThese findings provide further insight into elucidating the advantages of combination therapy with HDAC and PLD2 inhibitors over single-agent strategies for the treatment of cancer.
Highlights
Histone deacetylase (HDAC) inhibitors are promising anticancer drugs but their effect on tumor treat‐ ment has been disappointing mainly due to the acquisition of HDAC inhibitor resistance
HDAC inhibitors upregulate expression of phospholipase D2 (PLD2) We investigated whether HDAC inhibitors affect the expression of PLD2
The HDAC inhibitors upregulated the expression of PLD2 protein and increased the level of acetylated histone 4 in the cells, as determined by western blot assay using the antibody to PLD2 (Fig. 1a)
Summary
Histone deacetylase (HDAC) inhibitors are promising anticancer drugs but their effect on tumor treat‐ ment has been disappointing mainly due to the acquisition of HDAC inhibitor resistance. PLD2 point mutations have been detected in patients with breast cancer [21], and cell invasion of highly metastatic cancer cells is dependent on PLD2 [22]. These reports suggest that upregulation of PLD2 is involved in oncogenic signaling and tumorigenesis. We show that expression of PLD2 is upregulated by HDAC inhibitors, and confers resistance to HDAC inhibitors in breast cancer cells. Combination therapy with SAHA and PLD2 inhibitor significantly suppressed cell proliferation and angiogenesis and enhanced apoptosis of breast cancer cells, suggesting that combined treatment with these drugs might offer a promising therapeutic approach to the treatment of cancer by overcoming resistance to HDAC inhibitors
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
