Inhibition of HDACs-EphA2 Signaling Axis with WW437 Demonstrates Promising Preclinical Antitumor Activity in Breast Cancer

Tao Zhang; Jingjie Li; Xiaojun Ma; Yang Yang; Wei Sun; Wangrui Jin; Lei Wang; Yuan He; Feifei Yang; Zhengfang Yi; Yingqi Hua; Mingyao Liu; Yihua Chen; Zhengdong Cai

doi:10.1016/j.ebiom.2018.05.003

Inhibition of HDACs-EphA2 Signaling Axis with WW437 Demonstrates Promising Preclinical Antitumor Activity in Breast Cancer

EBioMedicine. 2018 May:31:276-286. doi: 10.1016/j.ebiom.2018.05.003.

Authors

Tao Zhang¹, Jingjie Li², Xiaojun Ma³, Yang Yang⁴, Wei Sun³, Wangrui Jin⁴, Lei Wang³, Yuan He⁴, Feifei Yang⁵, Zhengfang Yi⁴, Yingqi Hua⁶, Mingyao Liu⁷, Yihua Chen⁸, Zhengdong Cai⁹

Affiliations

¹ Department of Orthopedics, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200080, China; Shanghai Bone Tumor Institution, Shanghai 201620, China. Electronic address: zhangtaoabc@2008.sina.com.
² Institute of Translational Medicine, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200080, China.
³ Department of Orthopedics, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200080, China.
⁴ Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences, School of Life Sciences, East China Normal University, 500 Dongchuan Road, Shanghai 200241, China.
⁵ School of biological science and technology, University of Jinan, Jinan, Shandong Province 250022, China.
⁶ Department of Orthopedics, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200080, China; Shanghai Bone Tumor Institution, Shanghai 201620, China.
⁷ Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences, School of Life Sciences, East China Normal University, 500 Dongchuan Road, Shanghai 200241, China; Center for Cancer and Stem Cell Biology, Institute of Biosciences and Technology, Texas A&M University Health Science Center, Houston, TX 77030, USA.
⁸ Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences, School of Life Sciences, East China Normal University, 500 Dongchuan Road, Shanghai 200241, China. Electronic address: yhchen@bio.ecnu.edu.cn.
⁹ Department of Orthopedics, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200080, China; Shanghai Bone Tumor Institution, Shanghai 201620, China. Electronic address: caizhengdong@sjtu.edu.cn.

Abstract

Histone deacetylase inhibitors (HDACi) are small molecules targeting epigenetic enzymes approved for hematologic neoplasms, which have also demonstrated clinical activities in solid tumors. In our present study, we screened our internal compound library and discovered a novel HDACi, WW437, with potent anti-breast cancer ability in vitro and in vivo. WW437 significantly inhibited phosphorylated EphA2 and EphA2 expression. Further study demonstrated WW437 blocked HDACs-EphA2 signaling axis in breast cancer. In parallel, we found that EphA2 expression positively correlates with breast cancer progression; and combined use of WW437 and an EphA2 inhibitor (ALW-II-41-27) exerted more remarkable effect on breast cancer growth than either drug alone. Our findings suggested inhibition of HDACs-EphA2 signaling axis with WW437 alone or in combination with other agents may be a promising therapeutic strategy for advanced breast cancer.

Keywords: Breast cancer; EphA2; Growth; HDACs; Metastasis; WW437.

MeSH terms

Antineoplastic Agents / pharmacology*
Breast Neoplasms* / drug therapy
Breast Neoplasms* / metabolism
Breast Neoplasms* / pathology
Cell Line, Tumor
Drug Screening Assays, Antitumor
Ephrin-A2 / biosynthesis*
Female
Gene Expression Regulation, Neoplastic / drug effects*
Histone Deacetylase Inhibitors / pharmacology*
Humans
Neoplasm Proteins / biosynthesis*
Receptor, EphA2
Signal Transduction / drug effects*

Substances

Antineoplastic Agents
EPHA2 protein, human
Ephrin-A2
Histone Deacetylase Inhibitors
Neoplasm Proteins
Receptor, EphA2