Pracinostat (SB939), a histone deacetylase inhibitor, suppresses breast cancer metastasis and growth by inactivating the IL-6/STAT3 signalling pathways

Life Sci. 2020 May 1:248:117469. doi: 10.1016/j.lfs.2020.117469. Epub 2020 Feb 25.

Abstract

Aims: Histone deacetylases inhibitors have shown favorable antitumor activity in clinical investigations. In the present study, we assessed the effects of a novel hydroxamic acid-based HDAC inhibitor, SB939, on breast cancer metastasis and tumor growth and characterized the underlying molecular mechanisms.

Main methods: MTS, Wound-healing, and Transwell chamber invasion assays were used to detect the inhibition effects of SB939 on proliferation, migration, and invasion of breast cancer cells. Western blot, cellular immunofluorescence, and EMSA were used to explore the molecular mechanism of SB939 in suppressing breast cancer metastasis. MDA-MB-231 subcutaneous tumor-bearing model of nude mice and the spontaneous metastasis model of breast cancer were both applied to verify in vivo anti-tumor growth and anti-metastatic effects.

Key findings: Our results demonstrated that SB939 at 0.5-1 μmol/L markedly impaired the chemotactic motility of breast cancer cells. SB939 reversed epithelial-mesenchymal transition (EMT) process, as evidenced by upregulation E-cadherin expression and downregulation expressions of N-cadherin and vimentin through increasing the levels of ac-histone H3 and H4 and drecreasing the expressiongs of HDAC 5 and 4. This cascade inhibition mediated by SB939 was well interpreted by inactivating phosphorylation of STAT3, blocking its DNA-binding activity, and decreasing the expressions of STAT3-dependent target genes, including MMP2 and MMP9. Furhtermore, we found that SB939 significantly inhibited breast cancer metastasis and tumor growth in vivo and showed superior anti-tumor properties compared with SAHA in two breast cancer animal models.

Significance: Our findings indicate that SB939 may be an effective therapeutic option for treating advanced breast cancer.

Keywords: Breast cancer; EMT; HDACs; SB939; Tumor metastasis.

MeSH terms

  • Animals
  • Antigens, CD / genetics
  • Antigens, CD / metabolism
  • Antineoplastic Agents / pharmacology*
  • Benzimidazoles / pharmacology*
  • Breast Neoplasms / drug therapy*
  • Breast Neoplasms / genetics
  • Breast Neoplasms / metabolism
  • Breast Neoplasms / pathology
  • Cadherins / genetics
  • Cadherins / metabolism
  • Cell Line, Tumor
  • Cell Movement / drug effects
  • Cell Proliferation / drug effects
  • Epithelial-Mesenchymal Transition / drug effects
  • Epithelial-Mesenchymal Transition / genetics
  • Female
  • Gene Expression Regulation, Neoplastic*
  • Histone Deacetylase Inhibitors / pharmacology*
  • Histone Deacetylases / genetics
  • Histone Deacetylases / metabolism
  • Histones / genetics
  • Histones / metabolism
  • Humans
  • Interleukin-6 / genetics
  • Interleukin-6 / metabolism
  • Lung Neoplasms / drug therapy*
  • Lung Neoplasms / genetics
  • Lung Neoplasms / metabolism
  • Lung Neoplasms / secondary
  • Mice
  • Mice, Nude
  • Repressor Proteins / antagonists & inhibitors
  • Repressor Proteins / genetics
  • Repressor Proteins / metabolism
  • STAT3 Transcription Factor / genetics
  • STAT3 Transcription Factor / metabolism
  • Signal Transduction
  • Tumor Burden / drug effects
  • Vimentin / genetics
  • Vimentin / metabolism
  • Xenograft Model Antitumor Assays

Substances

  • Antigens, CD
  • Antineoplastic Agents
  • Benzimidazoles
  • CDH1 protein, human
  • CDH2 protein, human
  • Cadherins
  • Histone Deacetylase Inhibitors
  • Histones
  • IL6 protein, human
  • Interleukin-6
  • Repressor Proteins
  • SB939 compound
  • STAT3 Transcription Factor
  • STAT3 protein, human
  • VIM protein, human
  • Vimentin
  • HDAC4 protein, human
  • Histone Deacetylases