A histone deacetylase inhibitor enhances expression of genes inhibiting Wnt pathway and augments activity of DNA demethylation reagent against nonsmall-cell lung cancer

Jiunn Min Shieh, Yen An Tang, Fu Han Hu, Wei Jan Huang, Ying Jan Wang, Jayu Jen, Sheng You Liao, Ying Hung Lu, Ya Ling Yeh, Tseng Wei Wang, Pinpin Lin, Yi Ching Wang

Research output: Contribution to journalArticle

9 Citations (Scopus)

Abstract

Development of new inhibitors targeting histone deacetylases (HDACs) with improved efficacy for solid tumor therapy is urgently needed. Here, we report the development of a novel HDAC inhibitor TMU-35435 and verify it as a single agent and in combination treatment with DNA demethylation reagent 5-aza-2′-deoxycytidine (5-aza-dC) in lung cancer preclinical models. TMU-35435 exerted cancer-specific cytotoxicity via mitochondria-mediated apoptosis. Expression microarrays revealed a unique TMU-35435-induced gene networks enriched in biological processes, including “negative regulation of cell proliferation” and “Wnt receptor signaling pathway” compared to FDA-approved HDAC inhibitor SAHA. TMU-35435 inhibited tumor growth with good pharmacokinetic properties and safety features in lung orthotopic and subcutaneously implanted xenograft models. TMU-35435 and 5-aza-dC showed synergistic antitumor effects through reactivation of tumor suppressor genes and those genes encoding negative regulators of Wnt signaling pathway in vitro and in vivo. Some genes showed additive inhibition of DNA methylation upon TMU-35435 and 5-aza-dC combined treatment. Our findings suggested that TMU-35435 is a potential HDAC inhibitor for lung cancer treatment as a single agent and in combination with 5-aza-dC.

Original languageEnglish
Pages (from-to)2375-2386
Number of pages12
JournalInternational Journal of Cancer
Volume140
Issue number10
DOIs
Publication statusPublished - May 15 2017

Fingerprint

decitabine
Wnt Signaling Pathway
Histone Deacetylase Inhibitors
Histone Deacetylases
Non-Small Cell Lung Carcinoma
Gene Expression
DNA
Lung Neoplasms
Wnt Receptors
Biological Phenomena
Neoplasms
Gene Regulatory Networks
DNA Methylation
Tumor Suppressor Genes
Heterografts
Genes
Mitochondria
Pharmacokinetics
Cell Proliferation
Apoptosis

Keywords

  • 5-aza-2′-deoxycytidine
  • histone deacetylase inhibitor
  • lung cancer
  • Wnt signal

ASJC Scopus subject areas

  • Medicine(all)
  • Oncology
  • Cancer Research

Cite this

A histone deacetylase inhibitor enhances expression of genes inhibiting Wnt pathway and augments activity of DNA demethylation reagent against nonsmall-cell lung cancer. / Shieh, Jiunn Min; Tang, Yen An; Hu, Fu Han; Huang, Wei Jan; Wang, Ying Jan; Jen, Jayu; Liao, Sheng You; Lu, Ying Hung; Yeh, Ya Ling; Wang, Tseng Wei; Lin, Pinpin; Wang, Yi Ching.

In: International Journal of Cancer, Vol. 140, No. 10, 15.05.2017, p. 2375-2386.

Research output: Contribution to journalArticle

Shieh, Jiunn Min ; Tang, Yen An ; Hu, Fu Han ; Huang, Wei Jan ; Wang, Ying Jan ; Jen, Jayu ; Liao, Sheng You ; Lu, Ying Hung ; Yeh, Ya Ling ; Wang, Tseng Wei ; Lin, Pinpin ; Wang, Yi Ching. / A histone deacetylase inhibitor enhances expression of genes inhibiting Wnt pathway and augments activity of DNA demethylation reagent against nonsmall-cell lung cancer. In: International Journal of Cancer. 2017 ; Vol. 140, No. 10. pp. 2375-2386.
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