A new histone deacetylase inhibitor enhances radiation sensitivity through the induction of misfolded protein aggregation and autophagy in triple-negative breast cancer

Hui Wen Chiu, Ya Ling Yeh, Sheng Yow Ho, Yuan Hua Wu, Bour Jr Wang, Wei Jan Huang, Yuan Soon Ho, Ying Jan Wang, Li Ching Chen, Shih Hsin Tu

Research output: Contribution to journalArticle

Abstract

Radiation therapy (RT) is one of the main treatments for triple-negative breast cancer (TNBC). However, many patients experience RT failure due to the metastatic potential of RT and the radiation resistance of several cancers. Histone deacetylase inhibitors (HDACis) can serve as radiosensitizers. In this study, we investigated whether a novel HDACi, TMU-35435, could reinforce radiosensitivity through the induction of misfolded protein aggregation and autophagy in TNBC. Significantly enhanced toxicity was found for the combination treatment compared with TMU-35435 or irradiation (IR) treatment alone in TNBC cells. The combination treatment induced misfolded protein aggregation and TMU-35435 inhibited the interaction of HDAC6 with dynein. Furthermore, the combined treatment induced endoplasmic reticulum (ER) stress but did not trigger apoptosis. In addition, the combination treatment caused autophagic cell death. Tumor growth in the mouse of model orthotopic breast cancer was suppressed by the combination treatment through the induction of ER stress and autophagy. These findings support the future evaluation of the novel HDACi TMU-35435, as a potent radiosensitizer in TNBC.

Original languageEnglish
Article number1703
JournalCancers
Volume11
Issue number11
DOIs
Publication statusPublished - 2019 Nov

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Triple Negative Breast Neoplasms
Histone Deacetylase Inhibitors
Radiation Tolerance
Autophagy
Proteins
Endoplasmic Reticulum Stress
Radiotherapy
Therapeutics
Dyneins
Neoplasms
Radiation
Apoptosis
Breast Neoplasms
Growth

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

Cite this

Chiu, Hui Wen ; Yeh, Ya Ling ; Ho, Sheng Yow ; Wu, Yuan Hua ; Wang, Bour Jr ; Huang, Wei Jan ; Ho, Yuan Soon ; Wang, Ying Jan ; Chen, Li Ching ; Tu, Shih Hsin. / A new histone deacetylase inhibitor enhances radiation sensitivity through the induction of misfolded protein aggregation and autophagy in triple-negative breast cancer. In: Cancers. 2019 ; Vol. 11, No. 11.
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A new histone deacetylase inhibitor enhances radiation sensitivity through the induction of misfolded protein aggregation and autophagy in triple-negative breast cancer. / Chiu, Hui Wen; Yeh, Ya Ling; Ho, Sheng Yow; Wu, Yuan Hua; Wang, Bour Jr; Huang, Wei Jan; Ho, Yuan Soon; Wang, Ying Jan; Chen, Li Ching; Tu, Shih Hsin.

In: Cancers, Vol. 11, No. 11, 1703, 11.2019.

Research output: Contribution to journalArticle

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AU - Wang, Ying Jan

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AU - Tu, Shih Hsin

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