Chemoresistance in the Human Triple-Negative Breast Cancer Cell Line MDA-MB-231 Induced by Doxorubicin Gradient Is Associated with Epigenetic Alterations in Histone Deacetylase

Jeonghun Han; Wanyoung Lim; Daeun You; Yisun Jeong; Sangmin Kim; Jeong Eon Lee; Tae Hwan Shin; Gwang Lee; Sungsu Park

doi:10.1155/2019/1345026

Chemoresistance in the Human Triple-Negative Breast Cancer Cell Line MDA-MB-231 Induced by Doxorubicin Gradient Is Associated with Epigenetic Alterations in Histone Deacetylase

J Oncol. 2019 Jun 2:2019:1345026. doi: 10.1155/2019/1345026. eCollection 2019.

Authors

Jeonghun Han^{1

2}, Wanyoung Lim³, Daeun You⁴, Yisun Jeong⁴, Sangmin Kim⁵, Jeong Eon Lee^{4

5}, Tae Hwan Shin⁶, Gwang Lee⁶, Sungsu Park^{2

7}

Affiliations

¹ Regenerative Medicine and Cell Therapy Institute, Seoul National University Bundang Hospital, Seongnam 13620, Republic of Korea.
² School of Mechanical Engineering, Sungkyunkwan University, Suwon 16419, Republic of Korea.
³ Department of Biomedical Engineering, Sungkyunkwan University, Suwon 16419, Republic of Korea.
⁴ Department of Health Sciences and Technology, Samsung Advanced Institute for Health Sciences and Technology (SAIHST), Sungkyunkwan University, Seoul 06351, Republic of Korea.
⁵ Breast Cancer Center, Samsung Medical Center, Seoul 06351, Republic of Korea.
⁶ Department of Physiology, Ajou University School of Medicine, Suwon 16499, Republic of Korea.
⁷ Biomedical Institute for Convergence at SKKU (BICS), Sungkyunkwan University, Suwon 16419, Republic of Korea.

Abstract

Chemoresistance is one of the major causes of therapeutic failure in breast cancer patients. In this study, the mechanism of chemoresistance in human triple-negative breast cancer (TNBC) cells (MDA-MB-231) induced by doxorubicin (DOX) gradient was investigated. These DOX-resistant cells showed higher drug efflux rate, increased anchorage-independent growth when cultured in suspension, and increased tumor-forming ability in nude mice, compared to the wild-type MDA-MB-231 cells. RNA sequencing analysis showed an increase in the expression of genes involved in membrane transport, antiapoptosis, and histone regulation. Kaplan-Meier plot analysis of TNBC patients who underwent preoperative chemotherapy showed that the relapse free survival (RFS) of patients with high HIST1H2BK (histone cluster 1 H2B family member k) expression was significantly lower than that of patients with low HIST1H2BK expression. Quantitative real-time PCR confirmed that the level of HIST1H2BK expression was increased in resistant cells. The cytotoxicity analysis showed that the DOX resistance of resistant cells was reduced by treatment with a histone deacetylase (HDAC) inhibitor. Our results suggest that, in DOX-resistant cells, HIST1H2BK expression can be rapidly induced by the high expression of genes involved in membrane transport, antiapoptosis, and histone regulation. In conclusion, chemoresistance in MDA-MB-231 cells can occur in a relatively short period by DOX gradient via this previously known mechanism of resistance, and DOX resistance is dependent on the specificity of resistant cells to HDAC.